Stereoisomerism in the series of isoindole-based quaternary salts

Article abstract of DOI:10.1134/S107042801101009X

Steric structure of quaternary ammonium salts of the 3-[alkyl(aryl)amino]- 1-[alkyl(aryl)iminio]-1H-isoindole series was studied by ¹H NMR spectroscopy and X-ray analysis. The examined salts are characterized by E,E configuration of substituent

Full text of DOI:10.1134/S107042801101009X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 1, pp. 83–91. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © O.V. Gordienko, A.A. Tolmachev, M.Yu. Kornilov, R.I. Zubatyuk, O.V. Shishkin, 2011, published in Zhurnal Organicheskoi Khimii,
2011, Vol. 47, No. 1, pp. 85–93.
Stereoisomerism in the Series of Isoindole-Based
Quaternary Salts
O. V. Gordienkoa, A. A. Tolmacheva, M. Yu. Kornilova, R. I. Zubatyukb, and O. V. Shishkinb
a Taras Shevchenko Kiev National University, ul. Vladimirskaya 64, Kiev, 01601, Ukraine
e-mail: ov_hordiyenko@univ.kiev.ua
b Institute of Single Crystals, Ukrainian National Academy of Sciences, Kharkov, Ukraine
Received July 18, 2009
Abstract—Steric structure of quaternary ammonium salts of the 3-[alkyl(aryl)amino]-1-[alkyl(aryl)iminio]-
1
1H-isoindole series was studied by H NMR spectroscopy and X-ray analysis. The examined salts are
characterized by E,E configuration of substituents with respect to the exocyclic C–N bonds, and the presence of
ortho- and meta-substituents in the benzene rings on the nitrogen atoms gives rise to atropisomers. Sterically
hindered N-(2,4,6-trimethylphenyl) derivative was found to exist as Z,Z isomer which undergoes irreversible
thermal isomerization into the more stable E,E isomer through intermediate Z,E structure. The reactions of
1,1,3-trichloro-1H-isoindole with secondary aromatic amines having an electron-withdrawing substituent in the
ortho position in the presence of organic bases (triethylamine, N,N-dimethylbenzylamine) are accompanied by
decomposition of the latter and formation of unsymmetrically substituted salts of the 3-[alkyl(aryl)amino]-1-
(dialkyliminio)-1H-isoindole series, which contain both arylamine residue and dialkylamino group and are also
characterized by atropisomerism.
DOI: 10.1134/S107042801101009X
Compounds of the aminoimino-1H-isoindole series
can exist as different tautomers and geometric isomers
[1]. The latter appear due to the presence of double
exocyclic C=N bonds. For instance, 1,3-bis(aryl-
imino)-2,3-dihydro-1H-isoindoles generally exist as
mixtures of tautomers, as well as of Z,E isomers [2].
Their NMR spectra contain two sets of signals corre-
sponding to Z,E and Z,Z isomers. By contrast, quater-
nary isoindolium salts of the 3-amino-1-iminio-1H-
isoindole series are stable as E,E isomers of 1,3-bis-
[alkyl(aryl)amino] derivatives and Z,Z isomers of the
salts derived from cyclic fatty–aromatic amines [3].
3-Amino-1-iminio-1H-isoindole salts cannot be
synthesized by direct alkylation of the corresponding
bases, 1,3-bis(arylimino)-2,3-dihydro-1H-isoindoles;
however, such salts are readily available via nucleo-
philic replacement of chlorine in 1,1,3-trichloro-1H-
isoindole (I) by secondary amine residues in the pres-
ence of excess amine [3]. With a view to examine the
effect of steric factors on the state of equilibrium be-
tween stereoisomers we synthesized 1,3-bis(aryl-
amino)isoindolium salts having ortho substituents in
the aromatic ring. The reaction readily occurred in an-
hydrous aprotic solvent, such as chloroform, aceto-
Scheme 1.
Ar
CH2R
ClO4
Cl
N
(1) 2Et3N or excess amine
(2) H2O, NaClO4
+
2ArNHCH2R
N
N
Cl
N
Cl
CH2R
Ar
I
IIa–IId, IIIa–IIIg (E,E isomer)
II, R = H, Ar = 2-MeC6H4 (a), 2-MeOC6H4 (b), 2-ClC6H4 (c), 2,4,6-Me3C6H2 (d); III, R = Ph, Ar = Ph (a), 3-MeC6H4 (b),
2-MeC6H4 (c), 2-MeOC6H4 (d), 2-ClC6H4 (e), 2-BrC6H4 (f), 2,4,6-Me3C6H2 (g).
83

GORDIENKO et al.
84
Table 1. 1H NMR spectra of aryl{3-[(aryl)methylamino]-1H-isoindol-1-ylidene}methylammonium perchlorates IIa–IIc
at 298 K
Chemical shifts δ±0.02 ppm, J = 8 Hz
Comp.
no.
Stereoisomer
ratio, %
Solvent
other aromatic
protons, m
CH3, s
NCH3, s
4-H, 7-H, d.d 5-H, 6-H, d.d
CDCl3
57:43
2.30,2.32
2.41
4.00
4.32
5.79
6.25
7.13, 7.12
7.49
IIa
IIb
IIc
TFA-d
7.44–7.82
7.61
DMSO-d6
CDCl3
54:46
71:29
2.26, 2.28
3.87, 3.89
4.00
3.97
5.73
7.32
7.13
3.96
5.97, 5.99
6.50
7.08–7.73
7.28–7.95
7.20–7.75
7.50–7.90
7.64–7.94
7.60–8.10
TFA-d
4.31
DMSO-d6
CDCl3
3.83
3.95
5.95
7.35
7.17, 7.25
7.42
52:48
4.06, 4.04
4.21
5.92, 5.89
6.20
TFA-d
DMSO-d6
4.00, 3.98
5.85, 5.84
7.42
nitrile, or hexane, and in most cases another organic
base (e.g., triethylamine) can be used to bind liberated
hydrogen chloride. Salts IIa–IId and IIIa–IIIg were
isolated as readily crystallizable perchlorates which are
poorly soluble in water (see also [4] and references
therein).
cluded that the signal at δ 3.96 ppm belongs to the
N-methyl protons and that the singlets at δ 3.87 and
3.89 ppm arise from protons in the methoxy groups.
The chemical shifts of 4-H and 7-H are sensitive to
the solvent nature. They are fairly similar in the spectra
recorded from solutions in CDCl3 and DMSO-d6,
while in going to trifluoroacetic acid (CF3COOD) they
decrease by about 0.2–0.5 ppm, presumably as a result
of protonation of the endocyclic nitrogen atom and
formation of bis-quaternary salt.
It turned out that introduction of only one ortho
substituent did not lead to the appearance of Z,Z iso-
mer, and salts IIa–IIc and IIIa–IIIg have E,E configu-
ration. This follows from the characteristic diamag-
netic shift of signals from the 4-H and 7-H protons in
the isoindole residue to the region δ 5.7–6.5 ppm [3]
(Table 1) due to effect of ring current in the N-aryl
groups.
3.87
3.89
Me
Me
7.24 H
H7.24
4 O
7
O
H
H
5.99
5.99
Variation of the size of substituents does not change
the stereoisomer ratio. It might be expected that
increase in the size of the N-aryl group would affect
the torsion angle formed by the benzene ring and
heterocyclic fragment, which should affect the position
of the 4-H and 7-H signals. However, the presence of
a methyl group in the ortho position (compound IIa)
induces only a small diamagnetic shift (Δδ = 0.1 ppm,
DMSO-d6) as compared to unsubstituted salt [3], while
the 4-H and 7-H signals of salt IIb having ortho-
methoxy groups are displaced downfield (δ 5.95–
5.99 ppm). Signals in the spectrum of salt IIb in
CD2Cl2 solution were assigned using NOE technique.
Irradiation at a frequency corresponding to δ 3.89 ppm
increased the intensity of a doublet in the aromatic
region at δ 7.24 ppm, as well as the intensity of multi-
plet signal from 4-H and 7-H in the isoindole fragment.
Irradiation at a frequency corresponding to the other
methyl protons (δ 3.96 ppm) did not produce appreci-
able change of the spectral pattern. Therefore, we con-
N
N
N
3.96 Me
Me3.96
ClO4
Although substituents in the ortho positions of the
benzene rings do not favor formation of Z,Z isomers,
they give rise to atropisomerism related to restricted
internal rotation of the benzene rings about the C–N
bonds. This follows from the presence of two sets of
1
signals in the H NMR spectra of solutions of
N-methyl-substituted salts IIa–IIc (Table 1). The
1H NMR spectrum of salt IIa in CDCl3 at 298 K
contains two signals from protons in the ortho-methyl
groups with an intensity ratio of 57:43, a singlet from
the N-methyl groups, a doublet of doublets from 4-H
and 7-H, and two overlapped doublets of doublets
from 5-H and 6-H. Differences in the chemical shifts
become more appreciable in going to ortho-chloro
derivative IIc. The positions of all signals in the spec-
trum recorded from a solution in TFA-d are averaged;
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STEREOISOMERISM IN THE SERIES OF ISOINDOLE-BASED QUATERNARY SALTS
85
Table 2. 1H NMR spectra of aryl{3-[(aryl)benzylamino]-1H-isoindol-1-ylidene}benzylammonium perchlorates IIIa–IIIg
at 298 K
Chemical shifts δ±0.2 ppm, J = 8 Hz
Comp.
no.
Stereoisomer
ratio, %
Solvent
NCH2, d,
J = 14 Hz
NCH2, d,
J = 14 Hz
4-H, 7-H. 5-H, 6-H, other aromatic
CH3, s
Δδ
Δδ
d.d
d.d
protons, m
7.23–7.64
7.20–7.68
IIIa CDCl3
TFA-d
5.73
5.75
5.72
5.73
5.75
5.72
5.84
6.08
7.11
DMSO-d6
IIIb CDCl3
59:41
1.91, 2.13 5.63, 5.72 0.09 5.53, 6.00 0.69 5.77, 5.79
7.12
7.32
7.38 (C6H5),
7.04–7.60
TFA-d
61:39
57:43
42:58
2.01, 2.15 5.71, 5.85 0.14 5.53, 6.01 0.48
1.93, 2.20 5.66, 5.74 0.08 5.24, 6.10 0.86
3.68, 3.80 5.34, 5.78 0.44 5.09, 6.03 0.94
6.11
5.72
5.97
7.11–7.82
7.05–7.65
DMSO-d6
IIIc CDCl3
7.33 (C6H5),
6.95–7.69
TFA-d
58:42
3.73, 3.83 5.68, 5.77 0.09 5.51, 5.94 0.43
3.56, 3.69 5.50, 5.64 0.14 5.23, 5.91 0.68
6.32
7.40 (C6H5),
7.16–7.80
DMSO-d6
45:55
52:48
5.95
5.86
7.16
7.10
7.00–7.70
IIId CDCl3
2.38
5.59, 5.72 0.13 5.52, 5.79 0.27
7.35 (C6H5),
7.42 (o-H),
6.93–7.18
TFA-d
2.40
2.36
5.73
5.73
6.17
5.89
7.14–8.00
DMSO-d6
50:50
5.62, 5.78 0.16 5.55, 5.86 0.31
7.40 (C6H5),
7.25–7.83
IIIe CDCl3
TFA-d
53:47
50:50
57:43
44:56
5.37, 6.02 0.65 5.30, 6.10 0.80 5.86, 5.90 7.16, 7.27 7.20–7.70
5.32, 6.17 0.85 5.17, 6.28 1.11
5.68, 5.83 0.15 5.29, 6.16 0.87
5.28, 6.08 0.80 5.18, 6.18 1.00
6.04
5.86
5.83
7.24
7.71
7.04–7.68
7.42–8.00
DMSO-d6
CDCl3
IIIf
7.38 (C6H5),
7.15–7.85
TFA-d
46:54
46:54
5.31, 6.31 1.00 5.19, 6.39 1.20
5.56, 5.93 0.37 5.18, 6.24 1.06
6.07
5.85
7.30
7.06–8.00
7.43–8.10
DMSO-d6
in DMSO-d6 signals from particular N-methyl groups
can be observed; and the H NMR spectrum in CDCl3
contains two sets of signals from both N-methyl
protons and 4-H/7-H and 5-H/6-H.
The stereoisomer ratio of salts IIa–IIc ranges from
2:3 to 1:1, while one atropisomer of ortho-methoxy
derivative IIb in CDCl3 considerably predominates
(70%). No signal splitting was observed in the 1H NMR
spectra of salts IIa–IIc dissolved in TFA-d. Salts IId
and IIIg obtained, respectively, from N-methylmesi-
dine and N-benzylmesidine possess two ortho substit-
uents in each benzene ring on the nitrogen atoms;
therefore, they have no chiral elements and do not give
rise to atropisomers.
1
N-Benzyl derivatives IIIb–IIIf also displayed two
sets of signals with different intensities, corresponding
to the NCH2 protons (Table 2). These protons are dia-
stereotopic, and their signals appear as two AB systems
with larger or smaller difference in the chemical shifts.
Methylene protons in meta-substituted salt IIId are
also magnetically nonequivalent.
The ratio of atropisomers does not depend on the
1
1
The presence of two sets of signals in the H NMR
temperature: The H NMR spectrum of salt IIb in
spectra may be rationalized assuming that the exam-
ined compounds exist as mixtures of atropisomers,
symmetrical meso form and two enantiomers.
DMSO-d6 does not change on heating to 413 Κ. This
means that the stereoisomers are formed with approxi-
mately equal probabilities and are incapable of under-
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GORDIENKO et al.
86
R'
R'
RCH2
CH2R
CH2R
CH2R
N
N
N
R'
R'
N
N
N
N
N
N
CH2R
RCH2
R'
R'
meso
Enantiomers
going interconversion; i.e., they are approximately
equivalent in energy.
and bromo-substituted salts. On the other hand,
the maximal Δδ value for salt IIIb is observed in
DMSO-d6, and for IIIc, in CDCl3 (Table 2).
As follows from the spectral data for N-benzyl-
substituted salts IIIb–IIIf (Table 2), differences in the
chemical shifts of anisochronous protons in two stereo-
isomers are fairly large. The differences Δδ for meta
substituted derivative IIId are 0.27 and 0.13 ppm in
CDCl3 and 0.31 and 0.16 ppm in DMSO-d6. The Δδ
value for one stereoisomer of ortho-methyl-substituted
salt IIIb considerably increases (0.69 against 0.09 ppm
in CDCl3 and 0.86 against 0.08 ppm in DMSO-d6). As
the size of the substituent increases (in going from
methyl group in IIIb to bromine atom in IIIf), Δδ
successively rises in all solvents, e.g., to 1.00 ppm in
CDCl3. Simultaneously, the difference in the chemical
shifts of the corresponding protons in the second
stereoisomer also increases (from 0.09 to 0.80 ppm).
Rise in temperature differently affects the position
of signals from diastereotopic protons of two dia-
stereoisomers. The chemical shifts of the CH2 protons
in the stereoisomer of IIIc characterized by lower Δδ
value (0.14 ppm) remain unchanged as the temperature
rises to 433 K (DMSO-d6). The position of signals of
the second stereoisomer changes to a considerable
extent, from Δδ = 0.68 ppm at 298 K to 0.41 ppm at
433 K, approaching the corresponding signals of the
first stereoisomer. Presumably, the existence of tem-
perature dependence for only one isomer is the result
of internal nonequivalence of Δδi, and the value Δδ =
0.68 ppm includes the contributions of both conforma-
tional anisochronicity of Δδc (which depends on the
populations of all possible rotamers) and internal dif-
ference in the δ values for each conformer [5, 6].
Nonequivalence of the methylene protons is differ-
ent in different solvents. No anisochronicity is ob-
served for salt IIId in TFA-d, but it appears in going to
CDCl3 and DMSO-d6. The Δδ values for salts IIIb and
IIIc in TFA-d differ insignificantly; however, the dif-
ference Δδ between ortho-chloro and ortho-bromo
derivatives IIIe and IIIf exceeds 1 ppm in the same
solvent, and compound IIIf is characterized by the
largest Δδ values in this series (1.20 and 1.00 ppm).
On the whole, Δδ successively increases in going from
CDCl3 to DMSO-d6 and then to TFA-d for the chloro-
Increase of steric hindrances due to introduction of
bulky 2,4,6-trimethylphenyl (mesityl) group leads to
the formation of a mixture of Z,Z- and E,E-isomeric
iminium salts IId in the reaction of 1,1,3-trichloro-1H-
isoindole (I) with N-methylmesidine (Scheme 2). On
the other hand, the reaction of I with N-benzylmesi-
dine gives only one E,E isomer IIIg (like salts IIIa–
IIIc). The E,E and Z,Z isomers of IId in DMSO-d6 at
1
298 K display in the H NMR spectrum signals from
Scheme 2.
Ph
A–
Ph
Mes
Me
Mes
Me
A–
Mes
A–
N
N
N
N
N
N
+
(E,E)-IId
+
(Z,E)-IId
(E,E)-IId
N
N
N
Me
Mes
Mes
Me
Mes
(E,E)-IId
(Z,Z)-IId
(E,E)-IIIg
Mes = 2,4,6-Me3C6H2; A = ClO4–.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

STEREOISOMERISM IN THE SERIES OF ISOINDOLE-BASED QUATERNARY SALTS
87
Scheme 3.
R1
R1
N
H2O, NaClO4
I
+ +
2ArNHR3 3R12R2N
N
ClO4
R3
–R12R22N+ ClO4
N
Ar
(E)-IVa, (E)-IVb
Ar = 2-ClC6H4, R1 = R3 = Me, R2 = PhCH2 (a); Ar = 2-BrC6H4, R1 = R2 = Et, R3 = PhCH2 (b).
both stereoisomers with approximately equal inten-
sities. The signals were assigned taking into account
that the 4-H and 7-H signals of the E,E isomer appear
in a stronger field (δ 5.85 ppm, d.d, J = 8 Hz,) due to
shielding by ring current in the trimethylphenyl ring.
The 4-H and 7-H protons in the Z,Z isomer are not
shielded by the trimethylphenyl substitutents, and they
resonate in a weaker field (δ 8.33 ppm). The E,E
isomer is characterized by a doublet of doublets at
δ 7.28 ppm (J = 8 Hz) from 5-H/6-H and a singlet at
δ 3.86 ppm from the NCH3 protons. The Z,Z isomer
displays signals at δ 7.88 (J = 8 Hz, 5-H/6-H), 6.75
(m-H), and 3.92 ppm (NCH3).
The signal belonging to 4-H/7-H is transformed into
a doublet at δ 8.33 ppm with a coupling constant J of
8 Hz, and the second doublet with the same coupling
constant appears in a stronger field (δ 5.93 ppm). The
5-H/6-H signals constitute a part of an ABCD spin
system (δ 7.5 ppm). The intensity of signals from the
E,E isomer does not change.
The observed temperature-induced variations of the
spectral pattern are related to stereoisomer transforma-
tions involving disappearance of the Z,Z isomer and
appearance of the Z,E isomer. Magnetically anisotropic
effect of the trimethylphenyl ring in the latter spans
only one 4-H proton, and its signal is displaced upfield
(δ 5.93 ppm, d), whereas the 7-H signal remains in
a weak field (δ 8.33, d).
Raising the temperature to 363 K is accompanied
by reduction in the intensity of signals belonging to the
Z,Z isomer and appearance of new signals: two singlets
from the methyl groups in the mesityl substitutents,
two signals with equal intensities (δ 3.45 and 4.03 ppm)
from the N-methyl groups, and one signal correspond-
ing to meta protons in the mesityl group (δ 7.01 ppm).
Further raising the temperature to 413 K leads to
subsequent variations in the spectrum of compound
IId. The intensity of signals assigned to the Z,E isomer
decreases, and the intensity of signals from the E,E
isomer simultaneously increases. When the solution of
Table 3. 1H NMR spectra of isoindolium perchlorates IVa and IVb
Chemical shifts δ±0.02 ppm
Comp.
no.
Tempera-
ture, K
Ar
R1
R3
Solvent
NCH3,a CH2 NCH3,b CCH3 NCH3, CH2 4-Ha 5-H 6-H 7-Ha
IVa 2-ClC6H4 Me Me
CDCl3
303
303
308
453
303
308
373
3.97
3.91
3.88
3.89
3.86
3.87
3.82
3.87
3.86
3.84
3.78
3.80b
5.90 7.28 7.62 8.09
5.97 7.34 7.63 8.04
5.88 7.50 7.66 8.28
8.20
CD2Cl2
DMSO-d6
IVb 2-BrC6H4 Et PhCH2 CDCl3
DMSO-d6
4.29, 4.33c 1.59, 1.64c 4.84, 6.02d 5.84 7.28 7.71 8.08
4.24e
1.49e
5.08, 5.88d 5.93 7.43 7.69 8.13
4.22
4.24
1.49
1.51
5.13
5.85
5.93 7.46 7.73 8.16
a
b
c
d
e
Doublet, J = 7.7 Hz.
Broadened signal.
J = 7 Hz.
AB System, J = 14 Hz.
Broadened signal at 308 K in DMSO-d6.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

GORDIENKO et al.
88
IId was kept for 15 min at that temperature, the
1H NMR spectrum contained signals from only the E,E
isomer and was almost identical to the spectrum of salt
IIIg with analogous structure but having benzyl groups
on the nitrogen atoms, which originally had E,E struc-
ture. The spectrum of IId did not change after cooling
to 303 K and subsequent keeping for 3 days at room
temperature. When a solution of N-benzyl derivative
IIIg in CDCl3–(CD3)2CO (1:1) was cooled to 198 K,
The orientation of aromatic and alkyl substituents at
one of the exocyclic nitrogen atoms in perchlorates
IVa and IVb was the same as in symmetric salts IIa–
IId and IIIa–IIIg (E configuration). This followed
from the upfield shift of the 4-H signal (Table 3).
Magnetic nonequivalence of protons in the two methyl
groups on the nitrogen atom suggests a considerable
contribution of a structure in which the positive charge
is localized on the dimethylamino group.
1
its H NMR spectrum contained signals belonging to
only the E,E isomer.
5.97
8.04
H7
H4
The above findings led us to conclude that the E,E
isomer is thermodynamically more stable and that the
transformation Z,Z→Z,E→E,E is irreversible. This
transformation may follow rotational mechanism in-
volving rotation of all nitrogen-containing groups
about the single C–N bonds.
3.91
Me
N
N
N
Cl
3.87 Me
3.84 Me
ClO4
IVa
1
The H NMR signals of salt IVa were unambigu-
ously assigned on the basis of the results of NOE ex-
periments, as well as of the temperature variation of
the spectral pattern. Irradiation of protons in one of the
three methyl groups (δ 3.91 ppm, CD2Cl2) gave a re-
sponse on the 7-H doublet at δ 8.04 ppm. The intensity
of the latter insignificantly increased upon irradiation
of protons resonating at δ 3.87 ppm. Therefore, the
third signal (δ 3.84 ppm) was assigned to the methyl
protons in the methyl(2-chlorophenyl)amino group.
The reactions of 1,1,3-trichloro-1H-isoindole (I)
with secondary amines whose basicity is reduced due
to the presence of electron-withdrawing substituents
(such as chlorine or bromine atoms) should be carried
out using excess amine as base in acetonitrile. When
triethylamine or N,N-dimethylbenzylamine was added
to bind liberated hydrogen chloride, these amines
underwent decomposition with formation of unsym-
metrically substituted salts like IVa and IVb, as was
observed previously for weakly basic primary aromatic
amines [7] (Scheme 3).
Raising the temperature of a solution of salt IVa in
DMSO-d6 to 433 K resulted in broadening of the sing-
let at δ 3.78 ppm, whereas the two other signals (δ 3.82
and 3.88 ppm) were displaced toward each other, their
width remaining unchanged. The difference in their
chemical shifts was 0.02 ppm at 453 K. Simultaneous-
ly, the doublet at δ 5.88 ppm (4-H) gradually broad-
ened and then disappeared at 453 K, obviously due to
faster rotation of the methyl(2-chlorophenyl)amino
group and averaging of anisotropic effect of the
N-phenyl ring.
C23
C22
C25
N3
C24
C6
C8
C7
C5
N1
C4
C1
C2
C17
Like symmetric salts IIa–IIc and IIIb–IIIf, per-
chlorates IVa and IVb exist as mixtures of atrop-
C3
Br1
N2 C15
C16
C21
C18
1
isomers. The H NMR spectrum of o-bromophenyl
derivative IVb contained signals from diastereotopic
protons in the N-benzyl group (AB system, δ 5.08,
5.88 ppm) due to the presence of two enantiomers. The
difference in the chemical shifts of the methylene
protons increases to 1.18 ppm in CDCl3 (Table 3). The
signals from the two nonequivalent N-ethyl groups are
broadened at 308 K, and they become narrower on
heating to 373 K, the difference between the chemical
shifts (Δδ = 0.02 ppm) remaining unchanged. The
C9
C14
C10
C19
C20
C11
C12
C13
Structure of the molecule of 3-[benzyl(2-bromophenyl)-
amino]-1H-isoindol-1-ylidene(dimethyl)ammonium per-
chlorate (IVb) according to the X-ray diffraction data.
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STEREOISOMERISM IN THE SERIES OF ISOINDOLE-BASED QUATERNARY SALTS
89
same applies to the AB pattern formed by diastereo-
topic methylene protons in the benzyl group (Δδ =
0.72 ppm).
could exist as two enantiomers, while the presence of
two fragments in symmetric salts IIa–IIc and IIIb–
IIIf is responsible for the appearance of achiral meso
structure in addition to two enantiomers [5].
Our conclusions were confirmed by the X-ray dif-
fraction data for salt IVb with perchlorate as counter-
ion (see figure). Delocalization of the positive charge
over the NCNCN fragment leads to shortening of the
N2–C1 [1.329(7) Å] and N3–C8 bonds [1.315(7) Å]
(average length 1.36 Å [8]) and extension of the C1–N1
[1.339(7) Å] and C8–N1 bonds [1.368(8) Å] (average
length 1.28 Å). The N2 and N3 atoms have planar–
trigonal bond configuration. A small turn about the
C1–N2 bond is observed [the torsion angles C2C1N2C9
and N1C1N2C15 are 17.9(9) and –10.6(8)°, respec-
tively], and the methylene carbon atoms in the ethyl
groups lie in the isoindole ring plane [the torsion
angles C22N3C8C7 and C24N3C8N1 are 3(1)° and
–1.1(9)°, respectively]. The ethyl groups are oriented
in opposite directions almost orthogonally to the isoin-
dole ring plane [the torsion angles C8N3C22C23 and
C8N3C24C25 are 78.9(9)° and 104.6(8)°, respectively].
Substituents on N2 are arranged in such a way that the
bromophenyl ring is oriented cis with respect to the
benzene fragment of isoindole, despite obviously
stronger steric strain inducing rotation of the C9–C14
ring plane relative to the plane of the bicyclic fragment
[the torsion angle C1N2C9C10 is –60.9(8)°]. The
C16–C21 benzene ring is almost orthogonal to the iso-
indole ring plane [the torsion angle N2C15C16C17 is
–82.8(6)°]. Probably, such orientation of substituents is
stabilized by weak intramolecular C–H···π hydrogen
bond: C3–H3 ···X (H3 ···X 2.81 Å, C3–H3 ···X 143°,
where X is the centroid of the C9–C14 ring.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
WP-100SY spectrometer (100.13 MHz) and a Varian
Mercury 400 instrument (400 MHz) using tetramethyl-
silane as internal reference. Thin-layer chromatog-
raphy was performed using Silufol UV-254 plates. The
melting points were determined on a Boetius melting
point apparatus. Chloroform and acetonitrile were dis-
tilled over P2O5 just before use. 1,1,3-Trichloro-1H-
isoindole (I) was synthesized by reaction of phthal-
imide with phosphorus(V) chloride according to the
procedure described in [10].
X-Ray diffraction data for compound IVb. Tri-
clinic crystals, C25H25BrN3·ClO4, with the following
unit cell parameters (at 20°C): a = 10.531(3), b =
10.858(4), c = 12.384(4) Å; α = 94.99(3), β =
110.49(3), γ = 107.68(3)°; V = 1244(1) Å3; Mr =
–
546.84; Z = 2; space group I; dcalc = 1.460 g/cm3;
μ(MoKα) = 1.796 mm–1; F(000) = 560. The unit cell
parameters and intensities of 4547 reflections (4021 in-
dependent reflections with Rint = 0.100) were measured
on a Siemens P3/PC automatic four-circle diffractom-
eter (MoKα irradiation, graphite monochromator, 2θ/θ
scanning, 2θmax = 50°). A correction for absorption was
introduced semiempirically on the basis of the ψ-scan-
ning data. The structure was solved by the direct
method using SHELX97 software package [11]. The
positions of hydrogen atoms were determined by dif-
ference syntheses of electron density and were refined
according to the riding model with Uiso = nUeq (where
n = 1.5 for methyl hydrogen atoms, and n = 1.2 for the
other hydrogen atoms). The structure was refined with
the Cl–O bond length in the disordered perchlorate ion
constrained to 1.414(3) Å. Full-matrix least-squares
refinement (by F2) in anisotropic approximation for
non-hydrogen atoms was terminated at wR2 = 0.143 for
4021 reflections [R1 = 0.056 for 1937 reflections with
F > 4σ(F), S = 0.880]. The complete set of crystallo-
graphic data for compound IVb was deposited to
the Cambridge Crystallographic Data Centre (entry
no. CCDC 751355).
Molecules IVb in crystal are linked to dimers via
intermolecular stacking interactions between the isoin-
dole fragments of a reference molecule and that related
to it through the symmetry operation (–x, 1 – y, 2 – z)
(the distance between the ring centroids is 3.64 Å, and
their planes are strictly parallel). Also, a shortened
intermolecular contact was found in crystal: Br1···Br1
3.55 Å (–x, 2 – y, 2 – z) (the sum of the van der Waals
radii is 3.94 Å [9]).
The revealed stereochemical specificity of quater-
nary salts of the isoindole series are likely determined
by the presence in their molecules of a fragment which
can be regarded as aza vinylog of biphenyl (or quater-
nized Schiff base). This fragment firmly holds Z,Z
configuration of the phenyl rings about the C=N+
bond, which leads to atropisomerism. Salts IVa and
IVb possess only one such fragment, so that they
Alkyl{3-[alkyl(aryl)amino]-1H-isoindol-1-yli-
dene}(aryl)ammonium perchlorates IIa, IIb, IId
and IIIa–IIId (general procedure). A mixture of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

GORDIENKO et al.
90
20 mmol of the corresponding N-alkylaniline and
20 mmol of triethylamine in 20 ml of hexane was
added dropwise under stirring to a boiling solution of
2.20 g (10 mmol) of 1,1,3-trichloro-1H-isoindole (I) in
50 ml of hexane. The mixture was heated for 1 h under
reflux, and the yellow precipitate was filtered off,
dried, and dissolved in 100 ml of water. The aqueous
solution was filtered, and the product was precipitated
from the filtrate by adding NaClO4 and recrystallized
from ethanol.
8 Hz), 7.23–7.64 m (20H, Harom). Found, %: Cl 6.25;
N 7.13. C34H28ClN3O4. Calculated, %: Cl 6.13; N 7.27.
Benzyl{3-[benzyl(2-methylphenyl)amino]-1H-
isoindol-1-ylidene}(2-methylphenyl)ammonium
perchlorate (IIIb). Yield 82%, yellow crystals,
1
mp 272–273°C. H NMR spectrum (CDCl3), δ, ppm:
1.91s and 2.13 s (6H, NCH3), 5.63 m and 5.72 m (2H,
NCH2), 5.53 m and 6.00 m (2H, NCH2), 5.77 d.d and
5.79 d.d (2H, 4-H, 7-H, J = 8 Hz), 7.12 d.d (2H, 5-H,
6-H, J = 8 Hz), 7.38 m (10H, C6H5), 7.04–7.60 m (8H,
H
arom). Found, %: Cl 5.80; N 6.76. C36H32ClN3O4. Cal-
Methyl{3-[methyl(2-methylphenyl)amino]-1H-
isoindol-1-ylidene}(2-methylphenyl)ammonium
perchlorate (IIa). Yield 90%, yellow crystals, mp 259–
260°C. 1H NMR spectrum (CDCl3), δ, ppm: 2.30 s and
2.32 s (6H, CH3), 4.00 s (6H, CH3), 5.79 d.d (2H, 4-H,
7-H, J = 8 Hz), 7.12 d.d and 7.13 d.d (2H, 5-H, 6-H,
J = 8 Hz), 7.49 m (8H, Harom). Found, %: Cl 7.79;
N 9.53. C24H24ClN3O4. Calculated, %: Cl 7.83; N 9.26.
culated, %: Cl 5.85; N 6.93.
Benzyl{3-[benzyl(2-methoxyphenyl)amino]-1H-
isoindol-1-ylidene}(2-methoxyphenyl)ammonium
perchlorate (IIIc). Yield 80%, yellow crystals,
1
mp 190–191°C. H NMR spectrum (CDCl3), δ, ppm:
3.68 s and 3.80 s (6H, OCH3), 5.34 m and 5.78 m (2H,
NCH2), 5.09 m and 6.03 m (2H, NCH2), 5.97 d.d (2H,
4-H, 7-H, J = 8 Hz), 6.95–7.69 m (20H, 5-H, 6-H,
2-Methoxyphenyl{3-[(2-methoxyphenyl)methyl-
amino]-1H-isoindol-1-ylidene}methylammonium
perchlorate (IIb). Yield 70%, yellow crystals, mp 309–
310°C. 1H NMR spectrum (CDCl3), δ, ppm: 3.87 s and
3.89 s (6H, OCH3), 3.96 s (6H, NCH3), 5.97 d.d and
5.99 d.d (2H, 4-H, 7-H, J = 8 Hz), 7.13 d.d (2H, 5-H,
6-H, J = 8 Hz), 7.73–7.08 m (8H, Harom). Found, %:
Cl 7.71; N 9.06. C24H24ClN3O6. Calculated, %:
Cl 7.31; N 8.65.
Harom). Found, %: Cl 5.68; N 6.60. C36H32ClN3O6. Cal-
culated, %: Cl 5.56; N 6.58.
Benzyl{3-[benzyl(3-methylphenyl)amino]-1H-
isoindol-1-ylidene}(3-methylphenyl)ammonium
perchlorate (IIId). Yield 78%, yellow crystals,
1
mp 226–227°C. H NMR spectrum (CDCl3), δ, ppm:
2.38 s (6H, CH3), 5.59 m and 5.72 m (2H, NCH2),
5.52 m and 5.79 m (2H, NCH2), 5.86 d.d (2H, 4-H,
7-H, J = 8 Hz), 7.10 d.d (2H, 5-H, 6-H, J = 8 Hz),
7.35 m (10H, C6H5), 7.42 d (2H, o-H), 6.93–7.18 m
(8H, Harom). Found, %: Cl 5.33; N 7.18. C36H32ClN3O4.
Calculated, %: Cl 5.85; N 6.93.
(Z,Z/E,E)-Methyl{3-[methyl(2,4,6-trimethyl-
phenyl)amino]-1H-isoindol-1-ylidene}(2,4,6-tri-
methylphenyl)ammonium perchlorate (IId) was
synthesized in a similar way using chloroform as
solvent. When the reaction was complete, the mixture
was evaporated, the oily residue was treated with
100 ml of water, the aqueous solution was filtered, and
the product was precipitated from the filtrate as per-
chlorate by adding NaClO4. Yield 82%, yellow crys-
tals, mp 281–282°C. 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.97 s (6H, Z,Z, o-CH3), 2.15 s (9H, Z,Z, p-CH3
and E,E, o-CH3), 2.37 s (3H, E,E, p-CH3), 3.86 s (3H,
E,E, NCH3), 3.92 s (3H, Z,Z, NCH3), 5.85 d.d (1H,
E,E, 4-H, 7-H, J = 8 Hz), 6.75 s (2H, Z,Z, m-H), 7.15 s
(2H, E,E, m-H), 7.28 d.d (1H, E,E, 5-H, 6-H, J =
8 Hz), 7.88 d.d (1H, Z,Z, 5-H, 6-H, J = 8 Hz), 8.33 d.d
(1H, Z,Z, 4-H, 7-H, J = 8 Hz). Found, %: Cl 6.94;
N 8.11. C28H32ClN3O4. Calculated, %: Cl 6.96; N 8.24.
Condensation of 1,1,3-trichloro-1H-isoindole (I)
with weakly basic N-alkylanilines (general proce-
dure). A solution of 40 mmol of the corresponding
N-alkylaniline in 10 ml of acetonitrile was added drop-
wise under stirring to a solution of 2.20 g (10 mmol) of
1,1,3-trichloro-1H-isoindole (I) in 30 ml of acetoni-
trile. The mixture was heated for 1 h under reflux and
cooled, a saturated solution of NaClO4 was added, and
the yellow precipitate or oily substance was separated,
dried, and recrystallized from ethanol.
2-Chlorophenyl{3-[2-chlorophenyl(methyl)-
amino]-1H-isoindol-1-ylidene}methylammonium
perchlorate (IIc). Yield 85%, yellow crystals,
1
mp 207–208°C. H NMR spectrum (CDCl3), δ, ppm:
Benzyl{3-[benzyl(phenyl)amino]-1H-isoindol-1-
ylidene}phenylammonium perchlorate (IIIa). Yield
90%, yellow crystals, mp 233–234°C. H NMR spec-
4.04 s and 4.06 s (52:48, 6H, NCH3), 5.89 d.d and
5.92 d.d (2H, 4-H, 7-H, J = 8 Hz), 7.17 d.d and
7.25 d.d (2H, 5-H, 6-H, J = 8 Hz), 7.50–7.90 m (8H,
1
trum (CDCl3), δ, ppm: 5.73 s (4H, NCH2), 5.84 d.d
(2H, 4-H, 7-H, J = 8 Hz), 7.11 d.d (2H, 5-H, 6-H, J =
H
arom). Found, %: Cl 21.65; N 8.18. C22H18Cl3N3O4.
Calculated, %: Cl 21.54; N 8.49.
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STEREOISOMERISM IN THE SERIES OF ISOINDOLE-BASED QUATERNARY SALTS
91
Benzyl{3-[benzyl(2-chlorophenyl)amino]-1H-
isoindol-1-ylidene}(2-chlorophenyl)ammonium
perchlorate (IIIe). Yield 75%, yellow crystals,
7.55–7.78 m (4H, Harom). Found, %: Cl 17.70; N 10.70.
C17H17Cl2N3O4. Calculated, %: Cl 17.80; N 10.55.
3-[Benzyl(2-bromophenyl)amino]-1H-isoindol-1-
ylidene(dimethyl)ammonium perchlorate (IVb) was
synthesized in a similar way in the presence of
40 mmol of triethylamine. The crude product was re-
crystallized from ethanol. Yield 68%, yellow crystals,
1
mp 251–252°C. H NMR spectrum (CDCl3), δ, ppm:
5.37 m and 6.02 m (2H, NCH2), 5.30 m and 6.10 m
(2H, NCH2), 5.86 d.d and 5.90 d.d (2H, 4-H, 7-H, J =
8 Hz), 7.16 d.d and 7.27 d.d (2H, 5-H, 6-H, J = 8 Hz),
7.20–7.70 m (20H, C6H5, Harom). Found, %: Cl 16.25;
N 6.38. C34H26Cl3N3O4. Calculated, %: Cl 16.44;
N 6.49.
1
mp 201–202°C. H NMR spectrum (CDCl3), δ, ppm:
1.59 t and 1.64 t (6H, CH3, J = 7 Hz), 4.29 q and
4.33 q (4H, NCH2, J = 7 Hz), 4.84 m and 6.02 m (2H,
NCH2Ph, J = 14 Hz), 5.84 d (1H, 4-H, J = 7.7 Hz),
7.28 d.d (1H, 5-H), 7.71 d.d (1H, 6-H), 8.08 d (1H,
7-H, J = 7.7 Hz), 7.10–7.75 m (14H, Harom). Found, %:
N 7.45. C25H25BrClN3O4. Calculated, %: N 7.68.
Benzyl{3-[benzyl(2-bromophenyl)amino]-1H-
isoindol-1-ylidene}(2-bromophenyl)ammonium
perchlorate (IIIf). Yield 90%, yellow crystals, mp 247–
1
248°C. H NMR spectrum (CDCl3), δ, ppm: 5.28 m
and 6.08 m (2H, NCH2), 5.18 m and 6.18 m (2H,
NCH2), 5.83 d.d (2H, 4-H, 7-H, J = 8 Hz), 7.38 (10H,
C6H5), 7.15–7.85 m (10H, 5-H, 6-H, Harom). Found, %:
N 5.65. C34H26Br2ClN3O4. Calculated, %: N 5.71.
The authors are grateful to Prof. V.V. Negrebetskii
for his help in performing NMR studies.
REFERENCES
Benzyl{3-[benzyl(2,4,6-trimethylphenyl)amino]-
1H-isoindol-1-ylidene}(2,4,6-trimethylphenyl)am-
monium perchlorate (IIIg). Yield 75%, yellow crys-
1. Friedrichsen, W., Traulsen, T., Elguero, J., and Kat-
ritzky, A.R., Advances in Heterocyclic Chemistry, Kat-
ritzky, A.R., Ed., San Diego: Academic, 2000, vol. 76,
p. 129.
1
tals, mp 292–293°C. H NMR spectrum (CDCl3–
DMSO-d6, 1:1), δ, ppm: 1.84 s (12H, o-CH3), 2.40 s
(6H, p-CH3), 5.59 s (4H, CH2), 5.87 d.d (2H, 4-H, 7-H,
J = 8 Hz), 7.03 s (4H, m-H), 7.22 d.d (2H, 5-H, 6-H,
J = 8 Hz), 7.39 s (10H, C6H5). Found, %: Cl 5.30;
N 6.21. C40H40ClN3O4. Calculated, %: Cl 5.37; N 6.35.
2. Negrebetskii, V.V., Balitskaya, O.V., and Korni-
lov, M.Yu., Zh. Obshch. Khim., 1983, vol. 53, p. 2573.
3. Kornilov, M.Yu. and Makovetskii, V.P., Dokl. Akad.
Nauk USSR, Ser. B, 1974, p. 1013.
4. Closs, F., Gompper, R., Nagel, U., and Wagner, H.-U.,
2-Chlorophenyl{3-[2-chlorophenyl(methyl)-
amino]-1H-isoindol-1-ylidene}methylammonium
perchlorate (IVa). A mixture of 1.42 g (10 mmol) of
N-methyl-2-chloroaniline and 7.89 g (40 mmol) of
N,N-dimethylbenzylamine was added dropwise under
stirring to a solution of 2.20 g (10 mmol) of 1,1,3-tri-
chloro-1H-isoindole (I) in 50 ml of acetonitrile, and
the mixture was heated for 1 h under reflux. The
mixture gradually turned red and was left overnight.
The solvent was distilled off under reduced pressure,
and the dry residue was dissolved in 100 ml of water.
The solution was treated with activated charcoal on
heating to the boiling point and filtered, and compound
IVa was precipitated from the filtrate by adding
NaClO4 and recrystallized from water. Yield 60%,
Angew. Chem., 1987, vol. 99, p. 1068.
5. Eliel, E.L., Wilen, S.H., and Doyle, M.P., Basic Organic
Stereochemistry, New York: Wiley, 2001.
6. Raban, M., Tetrahedron Lett., 1966, vol. 7, p. 3105;
Mislow, K. and Raban, M., Topics in Stereochemistry,
Allinger, N.L. and Eliel, E.L., Eds., New York: Wiley:
1967, vol. 1, p. 1.
7. Gordienko, O.V., Negrebetskii, V.V., Ivanchenko, V.I.,
and Kornilov, M.Yu., Zh. Obshch. Khim., 1989, vol. 59,
p. 2771.
8. Burgi, H.-B. and Dunitz, J.D., Structure Correlation,
Weinheim: VCH, 1994, vol. 2, p. 741.
9. Zefirov, Yu.V. and Zorkii, P.M., Usp. Khim., 1989,
vol. 58, p. 713.
10. UK Patent no. 704595, 1954; Chem. Abstr., 1955,
1
yellow crystals, mp 138–139°C. H NMR spectrum
vol. 49, p. 7001.
(CDCl3), δ, ppm: 3.86 s (6H, NCH3), 3.97 s (3H,
NCH3), 5.90 d (1H, 4-H, J = 7.7 Hz), 7.28 d.d (1H,
5-H), 7.62 d.d (1H, 6-H), 8.09 d (1H, 7-H, J = 7.7 Hz),
11. Sheldrick, G.M., SHELX97. Programs for Crystal Struc-
ture Analysis (Release 97-2), Göttingen, Germany:
Universität Göttingen, 1998.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011