Remarkably strong polarization of amidine fragment in the crystals of 1-imino-1H-isoindol-3-amine

Article abstract of DOI:10.1007/s11224-012-0131-y

Results of the X-ray diffraction studies of 1-imino-1H-isoindol-3-amine and its derivatives reveal unusual distribution of bond lengths within the NH ₂-C=N amidine fragment in the considered crystals. In the crystal phase, single C-N bond is sh

Full text of DOI:10.1007/s11224-012-0131-y

Struct Chem
DOI 10.1007/s11224-012-0131-y
ORIGINAL RESEARCH
Remarkably strong polarization of amidine fragment
in the crystals of 1-imino-1H-isoindol-3-amine
•
Oleg V. Shishkin Irina S. Konovalova Roman I. Zubatyuk Gennady V. Palamarchuk
•
•
•
•
•
•
Svitlana V. Shishkina Angelina V. Biitseva Igor V. Rudenko Volodymyr A. Tkachuk
•
•
Mikhail Yu. Kornilov Olga V. Hordiyenko Jerzy Leszczynski
•
Received: 24 August 2012 / Accepted: 15 September 2012
Ó Springer Science+Business Media New York 2012
Abstract Results of the X-ray diffraction studies of
1-imino-1H-isoindol-3-amine and its derivatives reveal
unusual distribution of bond lengths within the NH2–C=N
amidine fragment in the considered crystals. In the crystal
phase, single C–N bond is shorter or at most has the same
length as double C=N bond, while in isolated molecules
both these bonds have expected lengths, according to the
calculations by MP2/6-311G(d,p) and MP2/cc-pvtz meth-
ods. It is demonstrated that so unusually strong polarization
of the amidine fragment is induced by polar environment in
solid state. This effect stabilizes the amino-imino tautomer
of 1-imino-1H-isoindol-3-amine, which becomes more
stable than the diimino tautomer possessing the lowest
energy in the gas phase.
Keywords Molecular structure ꢀ Amidine fragment ꢀ
Polar environment ꢀ Crystal phase ꢀ Quantum-chemical
calculations
Introduction
The 1-imino-1H-isoindol-3-amine 1, usually known as the
commercially available 1,3-diiminoisoindoline, is a key
compound for the synthesis of phthalocyanines and iso-
indoline pigments [1–3]. Derivatives of 1 are used also as
reagents for the synthesis of different biologically active
compounds [4, 5], analytical reagents [6], and other
materials [7, 8]. Therefore, fundamental data on structures
of these compounds is of great interest for understanding of
their reactivity.
NH
NH
O. V. Shishkin ꢀ I. S. Konovalova ꢀ R. I. Zubatyuk ꢀ
G. V. Palamarchuk ꢀ S. V. Shishkina
Division of Functional Materials Chemistry, SSI ‘‘Institute for
Single Crystals’’, National Academy of Science of Ukraine,
60 Lenina ave, Kharkiv 61001, Ukraine
N
NH
O. V. Shishkin (&)
Department of Inorganic Chemistry, V. N. Karazin National
University, 4 Svobody sq, Kharkiv 61077, Ukraine
e-mail: shishkin@xray.isc.kharkov.com
NH2
NH
A. V. Biitseva ꢀ I. V. Rudenko ꢀ V. A. Tkachuk ꢀ
M. Yu. Kornilov ꢀ O. V. Hordiyenko
1ai
1ii
Department of Organic Chemistry, National Taras Shevchenko
University of Kyiv, 64 Volodymyrska str, Kyiv 01601, Ukraine
In general, 1,3-diiminoisoindoline may exist in two
tautomeric forms, namely the amino-imino (1ai) and
diimino (1ii). Quantum-chemical calculations by AM1 and
HF methods [9, 10] indicated higher stability of the
J. Leszczynski
Interdisciplinary Center for Nanotoxicity, Department of
Chemistry and Biochemistry Jackson State University,
P.O. Box 17910, 1325 Lynch Street, Jackson, MS 39217, USA
123

Struct Chem
diimino tautomer 1ii. However, X-ray diffraction study of
1 led to the conclusion that in the crystal phase this com-
pound exists in the amino-imino tautomeric form 1ai [11].
Two polymorphic modifications of crystals of compound 1
were found differing in the orientation of the hydrogen
atom at the nitrogen of exocyclic C=N bond. In the case of
hydrazides of 1 both quantum-chemical calculations by
B3LYP/6-31G(d,p) method and X-ray diffraction, data
demonstrated that the 1ai tautomer is the most stable in gas
phase and crystals [7].
unusually strong polarization of the molecule by polar
environment in the crystalline phase. Usually, the positions
of the hydrogen atoms in X-ray diffraction studies are
located from difference maps of the electron density where
they correspond to the peaks of electron density. However,
in the case of nitrogen atom, both lone pair (for the C=N
fragment of heterocycle corresponding to 1ai tautomer)
and hydrogen atom (for the =C–NH fragment of the 1ii
tautomer) manifest themselves as peaks of electron density.
Taking into account the relatively small difference in dis-
˚
tances between the nitrogen atom and lone pair (ca. 0.6 A)
˚
and the hydrogen atom (0.8–0.9 A), it is possible to assign
Investigation of DMSO solution of 1 by NMR spec-
troscopy [11] led to conclusion about domination of the
diimino tautomer 1ii. Earlier it was suggested that this
may explain rapid proton exchange [12]. The same
results were obtained for solutions of some 4,5-disubsti-
tuted derivatives of 1 [9, 13]. However, it was found that
13C NMR spectra of 1 indicated an existence of a 5:1
mixture of 1ai and 1ii in DMSO-d6 solution based on 13C
chemical shift comparison with model compounds [14].
Earlier [15, 16] for 1,3-dialkyl (methyl, benzyl, t-butyl)
substituted diiminoisoindoline derivatives it was con-
cluded the prevalence of tautomeric form 1ai being reg-
istered at low temperature (173 K for dimethyl
derivative) in which the rapid proton exchange takes
place in the solution of CDCl3/(CD3)2CO (3:1), causing
averaged NMR spectra at ambient temperature. For 1,3-
diaryl-substituted derivatives of 1, the dependence of
tautomeric equilibrium on the solvent polarity, electronic
nature of substituents, temperature, and concentration was
demonstrated. The predominance of tautomeric form 1ii
is revealed in non-polar solvents, suggesting Z,E isom-
erism at the C=N double bonds. Increase of solvent
polarity results in the shift of tautomeric equilibrium to
1ai form. The dependence of dominating tautomer on
aryl p-substituent nature: from 1ii form for NO2 and
CH3CO to 1ai form entirely, in the case of donating
NMe2 group is also observed. Intermolecular rapid proton
exchange takes place in 1ai tautomer as well as between
1ai and 1ii forms with Z,E isomerization in the latter one.
The analysis of geometrical parameters of molecule 1 in
the crystal phase revealed unusual distribution of bond
lengths within the N=C–NH2 amidine fragment. The bond
length of formally single C–N bond is considerably shorter
than the length of formally double C=N bond. Similar
situation was observed for hydrazides of 1 [7], phenyl [17],
2,4-dimethylphenyl [18], and thiadiazolyltione derivative
[19].
the peak of lone pair to the hydrogen atom. Correctness of
the location of the hydrogen atoms may be checked by an
analysis of pattern of intermolecular hydrogen bonds in the
crystals. However, the network of H-bonds in the crystal of
both polymorphic modifications of 1 and its hydrazides is
suitable for both 1ai and 1ii tautomers [7, 11, 19].
On the other hand, for hydrazides of 1, all spectroscopic
data agree well with the 1ai tautomeric form [7]. On the
basis of quantum-chemical calculations by AM1 method of
tautomers of thiadiazolylthione derivative, the possibility
of existence of both tautomers in crystal phase was
assumed [19]. However, the authors were unable to locate
the suitable position for the hydrogen atom at cyclic
nitrogen from X-ray diffraction data.
Nevertheless, it is well known that the polar environ-
ment may lead to significant redistribution of electron
density and polarization of the molecules. Investigation of
polyhydrated complexes of nucleic acid bases demon-
strated significant changes of bond lengths due to polariz-
ing influence of water shell. It was found that the hydrated
cytosine cannot be described by canonical chemical for-
mula because of the significant contribution of zwitter-
ionic resonance form with single C–O- bond instead of
carbonyl group [20]. Strong deformations of molecular
geometry were observed also for uracil, thymine [21], and
guanine [22]. The same conclusions were derived from
Car-Parinello molecular dynamic simulations of water
solutions of nucleic acid bases [23]. Therefore, it is pos-
sible to suppose that the polar environment in the crystals
of 1 may be responsible for the significant redistribution of
electron density within the amidine fragment.
In order to shed a light on the reasons of such unusual
geometrical parameters of the amidine fragment in 1, we
investigated molecular structures of its derivatives without
NH fragments. In the present paper, we demonstrate that
strong polarization of the amidine fragment in the 1ai
tautomer of 1-imino-1H-isoindol-3-amine 1 is caused by
the polarizing influence of molecular surroundings in the
crystal phase.
There are two possible reasons of such unusual struc-
tural features of diiminoisoindoline, namely errors in the
determination of position of hydrogen atoms in the crystal
phase leading to wrong tautomeric form in the crystal or
123

Struct Chem
5
NR3
4
1 X=CH, R1=R2=R3=H
2 X=CH, R1=R2=H, R3=NHCOCH 3
3 X=CH, R1=R2=H, R3=NHCO(4-ClC 6H4)
4 X=CH, R1=R2=H, R3=NHCO(2-NH 2C6H4)
5 X=CH, R1=R2=H, R3=NHCO(C 5H4N)
6 X=CH, R1=R2=H, R3=thiadiazolylthione C 2N2S2H
7 X=CH, R1=R2=H, R3=Ph
N
3
X
2
8 X=CH, R1=R2=H, R3=(2,4-(CH3)2C6H3)
9 X=N, R1=R2=H, R3=(4-CH3C6H4)
10 X=CH, R 1=R2=CH3, R3=(2-NO2C6H4)
11 X=CH, R 1=R2=C2H5, R3=(4-CH3COC6H4)
1
NR1R2
Experimental
10, 11) and Oxford Diffraction Xcalibur-3 (structure 9) dif-
fractometers with graphite monochromated MoKa radiation
(k = 0.71073 A). Structures were solved by direct methods
˚
Synthesis
by SHELXTL program package [26]. Positions of the hydro-
gen atoms were located from the difference maps of electron
density and refined using riding model with Uiso = nUeq of
carrier atom where n = 1.5 for methyl groups and n = 1.2 for
other hydrogen atoms. Full-matrix least-squares refinement
against F2 was performed for non-hydrogen atoms within
anisotropic approximation. The final atomic coordinates, and
crystallographic data have been deposited to with the Cam-
bridge Crystallographic Data Centre, 12 Union Road, CB2
1EZ, UK (fax: ?44-1223-336033; e-mail: deposit@ccdc.
cam.ac.uk)and are available onrequest quotingthedeposition
numbers. Crystallographic data, parameters of experiment,
and crystal structure refinement are listed in Table 1.
1
The H NMR and 13C NMR spectra were measured on a
Mercury Varian-400 (400 MHz for 1H) instrument with
tetramethylsilane as an internal reference. IR spectrum was
recorded using a Nicolet Nexus 470 instrument as KBr
pellet. Melting point was determined using a Boetius
microscope hot plate apparatus.
Synthesis of the N,N-dimethyl-1-[(2-nitrophenyl)imino]-
1H-isoindol-3-amine (10) and the 1-(4-{[3-(diethylamino)-
1H-isoindol-1-ylidene]amino}phenyl)ethanone (11) was
described earlier [24]. The 5-[(4-methylphenyl)imino]-5H-
pyrrolo[3,4-b]pyridin-7-amine (9) was obtained according to
Kornilov and Makovetsky [25]. Pyridine-2,3-dicarbonitrile
(0.645 g, 5 mmol) was dissolved upon stirring and heating in
dry MeOH (10 mL), and catalytic amount of NaOH or freshly
generated solution of catalytic amount of NaOMe in MeOH
was added. Then solution of p-toluidine (0.535 g, 5 mmol) in
dry MeOH (10 mL) was added dropwise, and the resulting
greenish mixture was boiled for 3 h to complete solid pre-
cipitation. After cooling, the precipitate was filtered off and
washedwithMeOHanddried.Greenish–yellowsolid(0.68 g,
58 %), decomp.[250 °C. 1H NMR (400 MHz, [D6]DMSO/
CCl4 1:1, 20 °C): d = 2.28 (s, 3 H, CH3), 7.08 (d, 2 H,
J = 8.0 Hz, 30-H), 7.19(d, 2 H, J = 8.0 Hz, 20-H), 7.52(dd, 1
H, J = 4.8 Hz; J = 7.6 Hz, 3-H), 8.16 (dd 1 H, J = 1.2 Hz,
J = 7.6 Hz, 4-H), 8.20 (broad s, 1H, NH2), 8.67 (dd, 1 H,
J = 1.2 Hz, J = 4.8 Hz, 2-H), 8.7 (broad signal, 1H, NH2).
13C NMR (100 MHz, [D6]DMSO, 20 °C): d = 21.31 (CH3),
124.85, 125.83, 129.38, 129.45, 130.10, 133.63, 134.58,
147.20, 151.30, 155.15, 162.46, 170.79. IR (KBr disk, cm-1):
m = 1,505, 1,535, 1,638 (C=N), 2,915, 3,430, 3,445.
C14H12N4 (236.27): calcd. C 71.17, H 5.12, N 23.71; found C
71.48, H 5.14, N 23.41.
Quantum-chemical calculations
Molecular structure of tautomers of compound 1 was opti-
mized by means of second order Moller–Plesset perturbation
theory [27] with standard cc-pvtz [28] and 6-311G(d,p) [29]
basis sets. Character of stationary points was verified by the
Hessian calculations. Only positive eigenvalues were found.
Optimization of molecular structure of 1 in polar environ-
ment was performed using polarized continuum model
(PCM) [30] with water as solvent modeling polar environ-
ment of the molecule. Energy of the isolated tautomers/iso-
mers was also calculated at the CCSD(T)/cc-pvtz level of
theory using reference geometry obtained by MP2/cc-pvtz
method. Thermal corrections for Gibbs free energy were
taken from calculations of vibrational frequencies by MP2/
cc-pvtz method. All calculations were done by NWChem
[31], ORCA [32], and Gaussian 09 [33] programs.
X-ray diffraction study
Results and discussion
Single crystals of compounds 9–11 were obtained by slow
evaporation of their saturated methanol solutions. Data
collection was performed using Siemens P3/PC (structures
The aminoiminoisoindole 1 may exist in two tautomeric
forms namely the amino-imino (ai) and diimino (ii). Each
tautomer has a number of isomers differing in orientation
123

Struct Chem
of the hydrogen atoms at the exocyclic C=N double
bond with respect to the endocyclic nitrogen atom N3
(Scheme 1).
Table 1 Crystallographic data, parameters of experiments, and
structures refinement for structures 9-11
Crystal data
9
10
11
Earlier [11], two polymorphic modifications of crystals
of compound 1 were found. One polymorph (1trans) is
formed by only ai-trans isomer, while the second poly-
morph (1mix) contains both ai-cis and ai-trans isomers in
asymmetric part of unit cell. The most interesting feature of
molecule 1 in both polymorphs is unusual geometrical
parameters of the amidine fragment NH2–C=N. The bond
length of the C2–N1 formal single bond to the amino group
is significantly smaller than the lengths of the endocyclic
C2=N3 double bond (Table 2). Analysis of known data
related to structure of derivatives 1 (structures 2–8) indi-
cates that for all considered structures the lengths of these
two bonds do not agree with average values [34] for single
Formula
C14H12N4
236.28
C16H14N4O2
249.31
C20H21N3O
319.40
Triclinic
P-1
Mr/g mol-1
Crystal system
Space group
Triclinic
P-1
Monoclinic
P21/c
˚
a/A
7.0183 (5)
8.2963 (6)
10.8090 (7)
92.236 (5)
103.000 (6)
102.352 (6)
596.52 (7)
2
7.453 (2)
8.813 (2)
23.307 (7)
90
8.597 (2)
9.781 (2)
10.281 (2)
92.74 (2)
94.83 (2)
93.08 (2)
859.0 (3)
2
˚
b/A
˚
c/A
a/°
b/°
c/°
90
3
˚
V/A
1,419.9 (7)
4
Z
Dcalc (mg m-3
)
1.315
1.377
0.095
616
1.235
˚
and double C–N bonds (1.38 and 1.28 A, respectively).
˚
The bond distances vary within 1.309–1.329 A for the N1–
˚
C2 bond and 1.310–1.346 A for the C2=N3 bond. All
l (mm-1
F (000)
T/K
)
0.083
0.078
248
340
structures may be divided into two groups according to the
difference in these bond lengths. In the case of structures 1,
and 5–8 two C–N bonds have clearly different lengths with
double C2=N3 bond being longer than single N1–C2 bond.
These two bonds have very close bond lengths in mole-
cules 2–4 (Table 2). Taking into account that these two
groups of compounds differ only by substituent at the
imino nitrogen N5, it is difficult to explain such changes in
bond lengths just by polarization of p-system of isoindole
fragment due to substituent effect.
293
293
293
hmax/°
25.0
25.0
25.0
Reflections
collected/unique
5896/2056
3334/3115
3089/2886
Rint
0.024
0.063
0.051
Data/parameters
GooF on F2
2056/164
0.900
3115/201
0.948
2886/218
0.984
R1/wR2 (I [ 2r)
R1/wR2 (all data)
CCDC deposit no.
0.035/0.073
0.062/0.0800
896,998
0.073/0.251
0.194/0.251
896,999
0.081/0.250
0.211/0.250
897,000
Scheme 1 Isomers of
tautomers of compound 1
H
H
5
2
N
N
4
N
3
N
NH2
1
NH2
ai-cis
ai-trans
H
H
N
N
N
H
NH
NH
NH
N
N
H
N
H
ii-cisC
ii-trans
ii-cisN
H
123

Struct Chem
˚
Table 2 Bond lengths (A)
within the N1–C2–N3–C4–N5
fragment of derivatives of 1
according to X-ray diffraction
data
Compound
Tautomer
N1–C2
C2–N3
N3–C4
C4–N5
Ref
1mix
ai-cisa
ai-transa
ai-transb
ai-cis
1.320 (2)
1.317 (2)
1.311 (2)
1.327 (3)
1.329 (6)
1.322 (3)
1.309 (4)
1.311 (5)
1.313 (5)
1.317 (2)
1.314 (3)
1.311 (2)
1.324 (5)
1.332 (5)
1.327 (2)
1.333 (2)
1.334 (2)
1.335 (3)
1.310 (7)
1.328 (3)
1.342 (4)
1.331 (5)
1.338 (5)
1.331 (2)
1.346 (3)
1.317 (2)
1.338 (5)
1.324 (4)
1.395 (2)
1.388 (2)
1.390 (2)
1.393 (3)
1.394 (7)
1.392 (3)
1.390 (4)
1.367 (5)
1.379 (5)
1.395 (1)
1.408 (3)
1.406 (2)
1.391 (5)
1.388 (5)
1.281 (2)
1.280 (2)
1.377 (2)
1.297 (3)
1.275 (7)
1.299 (3)
1.286 (4)
1.309 (5)
1.307 (5)
1.288 (1)
1.280 (3)
1.276 (2)
1.279 (5)
1.266 (4)
[11]
1mix
[11]
1trans
[11]
2
3
4
5
6
[7]
ai-cis
[36]
ai-cis
[36]
ai-cis
[36]
ai-cis
[19]
ai-cis
[19]
7
ai-cis
[17]
8
ai-cis
[18]
a
Data for polymorph formed
by both ai-cis and ai-trans
9
ai-cis
This work
This work
This work
isomers
b
Data for polymorph formed
only by ai-trans isomer
10
11
ai-cis
ai-cis
Scheme 2 Resonance
structures of molecule 1
R3
N
R3
A
B
N
N
N
NR1R2
NR1R2
This assumption agrees well with variation of the N3–
C4 and C4–N5 bonds in molecules under consideration.
˚
These bonds vary within 1.390–1.394 A, 1.275–1.299 A
˚
˚
˚
for structures 2–4 and 1.367–1.408 A, 1.280–1.309 A for
structures 1, and 5–8. In all cases, bond lengths are quite
close to average values [34] for the corresponding single
˚
˚
(1.38 A) and double (1.28 A) C–N bonds. It should be
noted that these bond lengths do not depend on the char-
acter of substituent at the N5 atom (Table 2).
Thus, experimental data about 1-imino-1H-isoindol-3-
amines structure in crystal phase clearly indicate significant
contribution of zwitter-ionic resonance structure
B (Scheme 2) in total structure of the molecules. More-
over, in the case of the molecules 1 and 5–8, resonance
structure B dominates over the conventional structure A.
The same feature of molecular structure mentioned
above is observed in aza analog of 1-imino-1H-isoindol-3-
amine 9 where the benzene ring of isoindole fragment is
replaced by pyridine heterocycle (Fig. 1). Results of X-ray
diffraction study indicate that the lengths of the N1–C2 and
C2–N3 bonds are equal within triple standard deviation
(Table 2). This agrees well with significant contribution of
zwitter-ionic resonance structure B into total structure
of the molecule. The evidence of such strong polarization
Fig. 1 Structure of molecule 9 according to X-ray diffraction data.
Thermal ellipsoids are drawn at 50 % probability level
of the N1–C2–N3 fragment also is maintained by com-
parison of the signals of the NH2 group protons in the
1H NMR spectra of isoindole 8 [13] and aza derivative 9
that reveal as two broaden singlets with the difference in
chemical shifts of about 0.5 ppm. Therefore, the geometry
of the amidine fragment in this molecule is not sensitive to
the appearance of heteroatoms in the isoindole bicycle.
The existence of 1ai tautomeric form of compounds
under consideration is confirmed unambiguously by X-ray
diffraction study of crystals 10, 11 (Figs. 2, 3). In these
123

Struct Chem
molecules, the hydrogen atoms of the amino group are
replaced by alkyl groups. This excludes any errors in the
localization of the hydrogen atoms’ position at the nitrogen
atoms because of the absence of such atoms. However, the
analysis of experimental data indicates equivalence of the
N1–C2 and C2–N3 bond, the lengths of which are equal
within triple standard deviation (Table 2).
However, the results of quantum-chemical calculations
by MP2/6-311G(d,p) and MP2/cc-pvtz methods of isolated
molecule 1 completely disagree with experimental data for
the crystal phase. According to theoretic data (Table 3)
lengths of the N1–C2 and C2–N3 bonds are typical for
single and double C–N bonds. This indicates negligible
contribution of zwitter-ionic resonance structure B in total
structure of isolated molecule. Taking into account high
enough reliability of these methods of calculation of
molecular structure (see, for example, ref. [35]), it is pos-
sible to conclude that strong polarization of the amidine
fragment in the molecules 1–11 is not caused by intramo-
lecular interactions.
Fig. 2 Structure of molecule 10 according to X-ray diffraction data.
Thermal ellipsoids are drawn at 30 % probability level
Earlier similar strong polarization of molecules was
found for nucleic acid bases uracil, thymine, cytosine, and
guanine as a result of influence of polar environment in
polyhydrated complexes [20–22] or water solutions [23]. In
all cases, the polarizing influence of water shell causes
significant contribution of zwitter-ionic resonance struc-
tures which becomes dominating in the case of cytosine
[20]. Therefore, it is possible to suppose that the contra-
diction between results of quantum-chemical calculations
of isolated 1-imino-1H-isoindol-3-amine 1 and experi-
mental data for crystal phase is caused by the unusually
strong influence of polar environment in the crystals.
Fig. 3 Structure of molecule 11 according to X-ray diffraction data.
Thermal ellipsoids are drawn at 30 % probability level
˚
Table 3 Bond lengths (A), bond angles (°), and sum of bond angles
calculations by MP2/cc-pvtz and MP2/6-311G(d,p) methods of
isolated molecule and the molecule in polar environment modeled
by PCM
centered at the nitrogen atom of amino group (RNH2, °) within the
N1H2–C2=N3–C4=N5 fragment in the most stable amino-imino ai-
cis and diimino ii-cisC tautomers of 1 according to quantum-chemical
MP2/cc-pvtz
MP2/6-311G (d,p)
ai-cis
ii-cisC
ai-cis
ii-cisC
Isolated
PCM
Isolated
PCM
Isolated
PCM
Isolated
PCM
N1–C2
1.352
1.305
1.416
1.278
352.2
123.4
106.2
126.7
1.333
1.314
1.408
1.281
360
1.279
1.385
1.385
1.279
–
1.280
1.385
1.385
1.280
–
1.362
1.306
1.420
1.281
347.3
123.4
106.1
126.7
1.346
1.313
1.414
1.284
353.0
123.7
106.3
126.6
1.283
1.389
1.389
1.283
–
1.284
1.390
1.390
1.284
–
C2–N3
N3–C4
C4–N5
RNH2
N1–C2–N3
C2–N3–C4
N3–C4–C5
123.9
106.4
126.5
122.8
114.0
122.8
123.0
113.7
123.0
122.8
114.3
122.8
123.0
113.9
123.0
123

Struct Chem
Modeling of polarizing influence of environment may be
performed by PCM with water as the most polar solvent.
Investigation of the structure of nucleic acid bases [36]
demonstrated that although the results of PCM approach do
not reveal very strong changes of geometry observed in
polyhydrated complexes or water solutions, they correctly
reproduce the trend of such changes. Therefore, it is pos-
sible to expect that the optimized geometry of the molecule
1 obtained by PCM approach indicates the direction of
geometry change induced by the polar environment in
crystal phase.
Fig. 4 Structure of hydrogen bonded dimer in crystal 1mix [11]
Results of the calculations demonstrate that the appear-
ance of polar environment leads to the shortening of the
Analysis of the crystal structure of compounds 1–11
show existence of the N–HꢀꢀꢀN and N–HꢀꢀꢀO hydrogen
bonds with participation of the amidine fragment (Table 4).
In structures 1 and 7–9, the considered molecules form the
same centrosymmetric dimer stabilized by hydrogen bonds
between the amino group of one molecule and the N2 atom
of the second molecule (Fig. 4). In crystals 2–6, the amino
group and the N2 atom are involved in hydrogen bonding
with solvating water molecule and substituent at the N5
atom. However, in all structures, hydrogen bonds are rather
weak (Table 4) and they cannot induce significant changes
of geometry of molecule due to their formation, as it is
observed in the case of strong hydrogen bonds.
˚
N1–C1 bond (Dl = 0.016–0.019 A) and the elongation of
˚
the C2–N3 bond (Dl = 0.007–0.009 A). Thus, the differ-
˚
ence in these bond lengths decreases from 0.047–0.056 A
˚
for an isolated molecule to 0.019–0.033 A for the molecule
in polar environment (Table 3). This trend is in clear
agreement with the observed experimental data. It should be
noted that exocyclic double bond C4=N5 and neighboring
bond N3–C4 are not sensitive to the polarity of environ-
˚
ment, remaining almost unchanged (Dl = 0.001–0.008 A,
Table 3).
Taking into account the strong polarization of the ami-
dine fragment in crystal phase, it is interesting to investi-
gate if this effect is caused by some specific intermolecular
interactions in crystal phase or it results from just the
presence of polar environment in general. In the first case,
such intermolecular interactions should involve the amino
group and the N2 atom of isoindole bicycle.
However, the optimization geometry of hydrogen-bon-
ded dimer of molecule 1 (Fig. 4) by MP2/6-311G(d,p)
method demonstrates the significant polarization of the
amidine fragments. The N1–C2 bond becomes considerably
˚
˚
shorter (1.334 A, Dl = -0.028 A) and the C2–N3 bond is
˚
˚
longer (1.321 A, Dl = ?0.015 A) as compared to the
isolated molecule (Table 3). The N–HꢀꢀꢀN hydrogen bonds
Table 4 Geometrical parameters of hydrogen bonds with the par-
ticipation of the amino group and the N2 atom of the amidine frag-
ment in the crystals 1-9
˚
in optimized dimer also are shorter (HꢀꢀꢀN 1.89 A, N–HꢀꢀꢀN
174o) than in crystal phase (Table 4). However, they are
not strong enough to induce significant polarization of the
amidine fragment. Probably, the dipole–dipole interactions
between the molecules provide more important contribu-
tion in polarization of the amidine fragment in the mole-
cules under consideration. This assumption also agrees
well with geometrical parameters of the molecules 10, 11
where the proton-donating NH bonds are absent and the
amidine fragment is not involved in the formation of
hydrogen bonds at all.
˚
Compound
D–HꢀꢀꢀA
HꢀꢀꢀA A
D–HꢀꢀꢀA (°)
1mix
N1–HꢀꢀꢀN2
N1–HꢀꢀꢀN2
N1–HꢀꢀꢀN2
O–HꢀꢀꢀN2
N1–HꢀꢀꢀO
O–HꢀꢀꢀN2
N1–HꢀꢀꢀO
O–HꢀꢀꢀN2
N1–HꢀꢀꢀO
O–HꢀꢀꢀN2
N1–HꢀꢀꢀO
N1–HꢀꢀꢀO
N1–HꢀꢀꢀO
N1–HꢀꢀꢀN2
N1–HꢀꢀꢀN2
N1–HꢀꢀꢀN2
1.96
2.01
2.05
1.93
2.03
2.32
2.07
2.09
2.21
2.09
2.11
2.09
2.06
2.08
2.05
2.07
174
166
176
159
175
136
167
154
153
148
170
157
175
156
173
167
1trans
2
3
4
5
6
Taking into account strong polarization of the amidine
fragment of 1-imino-1H-isoindol-3-amine by polar envi-
ronment, it is possible to suppose that this effect may
influence also some properties of this compound. In par-
ticular, this concerns relative stability of tautomers and
isomers of 1. Results of calculations demonstrate that for
the isolated molecules, the diimino tautomer with the
hydrogen atoms oriented toward the benzene ring (ii-cisC)
is the most stable (Table 5). Slightly higher energy is
predicted for the ii-trans isomer of this tautomer. The 1ai
7
8
9
123

Struct Chem
polarizing influence of environment in the solid state. This
assumption is supported by the results of X-ray diffraction
study of 1-imino-1H-isoindol-3-amine derivatives con-
taining dialkylamino group where the amidine fragment of
the molecule is not involved in intermolecular interactions.
Nevertheless, in these structures, single and double C–N
bonds have almost equal lengths.
Table 5 Relative Gibbs free energy at 298 K (kcal/mol) of tautomers
of compound 1 calculated for the isolated molecules and molecules in
polar environment modeled by PCM
Tautomer
Isolated
PCM
MP2/
cc-pvtz
CCSDT/cc-pvtz//
MP2/cc-pvtz
MP2/
cc-pvtz
ii-cisC
ii-cisN
ii-trans
ai-cis
0
0
1.25
1.49
1.05
0
Modeling of polar environment by PCM of solvent
demonstrates a clear trend of shortening single and elon-
gation double C–N bonds. Similar results are obtained from
the optimized geometry of dimer of 1-imino-1H-isoindol-
3-amine 1 formed due to two equivalent N–HꢀꢀꢀN hydrogen
bonds between atoms of the amidine fragment, despite their
moderate strength. This indicates that the change in bond
lengths within the amidine fragment is caused by the
general influence of polar environment rather than some
specific intermolecular interactions.
1.28
0.30
1.21
4.76
1.21
0.25
1.38
4.99
ai-trans
1.14
tautomer is less stable, especially in the case of trans-iso-
mer (Table 5).
Appearance of polar environment results in drastic
changes of relative stability of tautomers (Table 5). Strong
polarization of the amidine fragment leads to significant
stabilization of the 1ai tautomer. The lowest energy is
revealed for the ai-cis isomer. However, the energy of all
other isomers of both tautomers is only slightly higher (less
than 1.5 kcal/mol). This agrees well with experimental
findings about equilibrium between two tautomers in
solutions [9, 11, 13].
Analysis of relative stability of tautomers/isomers of
1-imino-1H-isoindol-3-amine 1 demonstrates that the
appearance of polar environment results in the stabilization
of the 1ai tautomer, while the diimino tautomer is the most
stable in gas phase. Therefore, strong polarization of the
amidine fragment by polar environment represents some
kind of stabilizing effects which may be used for tuning of
properties of 1-imino-1H-isoindol-3-amine. Partially dou-
ble character of the C–NH2 bond of the amidine fragment
also may explain relatively low reactivity of amino group
of mono-substituted derivatives of 1 in the substitution
reactions with N-nucleophiles, such as of low basic amines,
N-acylhydrazides, amino acid esters, and hydrazides [7,
37], preferable condensation of thioamide function rather
than amidine one with a-halogen ketones, and at the same
time its readiness to react with active methylene com-
pounds, but not carbonyl group [38].
It should be noted that the geometrical parameters of the
diimino tautomer are not sensitive to the presence of polar
environment (Table 3). Therefore, it is possible to suggest
that the polarization of the amidine fragment represents the
stabilizing factor for the molecules under consideration.
Change of polarity of medium may be used for the tuning
of the molecular structure and properties of the aminoi-
mino/diimino derivatives of isoindole.
Conclusions
Results of X-ray diffraction studies of 1-imino-1H-isoin-
dol-3-amine 1 and its derivatives reveal unusual distribu-
tion of bond lengths within the NH2–C=N amidine
fragment. In the crystal phase, single C–N bond is shorter,
or at least has the same length as double C=N bond. This
effect may be explained by the dominating contribution of
zwitter-ionic resonance structure NH2?–C=N- into total
structure of molecules. Experimental data completely dis-
agree with the results of quantum-chemical calculations of
the isolated molecule by MP2/6-311G(d,p) and MP2/cc-
pvtz methods. According to theoretic data, both C–N bonds
have typical lengths corresponding to conventional struc-
ture of the amidine fragment.
References
1. Fernando-Lazaro F, Torres T, Hauschel B, Hanack M (1998)
Chem Rev 98:536
2. Radtke V, Erk P, Sens B (2002) In: Smith H (ed) Isoindoline
pigments, in high performance pigments. Wiley, Weinheim
3. Hirohashi R, Sakamoto K, Ohno-Okumura E (2004) Phthalocy-
anines as functional dyes. ICP, Tokyo
4. Grant EB, Guiadeen D, Singer M, Argentieri D, Hlasta DJ,
Wachter M (2001) Bioorg Med Chem Lett 11:2817
5. Butner L, Huang Y, Tse E, Hall IH (1996) Biomed Pharmacother
50:290
6. Callejon Mochnon M, Munoz Leyva JA (1986) Microchem J
34:83
7. Hordienko OV, Biitseva AV, Kornilov MY, Brosse N, Hocquet
A, Jamart-Gregoire B, Shishkin OV, Zubatyuk RI (2006) Eur J
Org Chem 12:2833
8. Hordienko OV, Rudenko IV, Biitseva AV, Turov AV, Arrault A,
Brosse N, Fabre O, Jamart-Gregoire B, Zubatyuk RI, Shishkin
OV (2009) Tetrahedron 65:6218
Taking into account the weak character of intermolec-
ular hydrogen bonds in the crystals of imino-1H-isoindol-
3-amines, it is possible to suggest that the deformation of
geometry of the amidine fragment is caused by the
123

Struct Chem
9. Lyubimtsev AV, Baranski A, Islyaikin MK, Smirnov RP (1997)
Chem Heterocycl Compd 27:435
26. Sheldrick GM (2008) Acta Crystallogr Sect A 64:112
27. Møller C, Plesset MS (1934) Phys Rev 46:618
10. Acker A, Hofman H-J, Cimiraglia R (1994) J Mol Struct
(THEOCHEM) 315:43
28. Kendall RA, Dunning TH Jr, Harrison RJ (1992) J Chem Phys
96:6796
11. Zhang Z-Q, Njus JM, Sandman DJ, Guo C, Foxman BM, Erk P,
Van Gelder R (2004) Chem Commun 886
12. Elguero J, Marzin C, Katritzky AR, Linda P (1976) In: Katritzky
AR, Boulton AJ (eds) Advances in Heterocyclic Chemistry,
Suppl. 1, The Tautomerism of Heterocycles. Academic Press,
New York
13. Pawlowski G, Hanack M (1980) Synthesis 4:287
14. Spiessens LI, Arteunis MJO (1988) Bull Soc Chim Belg 97:431
15. Negrebetskii VV, Balitskaya OV, Kornilov MY (1983) Russ J
Gen Chem 53:2573
16. Friedrichsen W, Traulsen T, Elguero J, Katritzky AR (2000)
Tautomerism of heterocycles: five-membered rings with one
heteroatom; advances in heterocyclic chemistry, vol 76. Aca-
demic Press, San Diego
17. Zhang Z-Q, Uth S, Sandman DJ, Foxman BM (2004) J Phys Org
Chem 17:769
18. Biitseva AV, Hordiyenko OV, Sukach VA, Vovk MV, Pichugin
KA, Konovalova IS, Shishkin OV (2008) Monatsh Chem 139:939
19. Shishkin OV, Kudrik EV, Islyaikin MK, Lyubimtsev AV, Siling
SA (1998) Russ Chem Bull 47:327
20. Shishkin OV, Gorb L, Leszczynski J (2000) J Phys Chem A
104:5357
21. Shishkin OV, Gorb L, Leszczynski J (2000) Int J Mol Sci 1:17
22. Sukhanov OS, Shishkin OV, Gorb L, Leszczynski J (2008) Struct
Chem 19:171
29. McLean AD, Chandler GS (1980) J Chem Phys 72:5639
30. Tomasi J, Mennucci B, Cammi R (2005) Chem Rev 105:2999
31. Valiev M, Bylaska EJ, Govind N, Kowalski K, Straatsma TP,
Van Dam HJJ, Wang D, Nieplocha J, Apra E, Windus TL, de
Jong WA (2010) Comp Phys Commun 181:1477
32. Neese F (2010) ORCA 2.8.0. Universitaet Bonn, Germany
33. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson
GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF,
Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K,
Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao
O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F,
Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN,
Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC,
Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M,
Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts
R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C,
Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth
GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas
O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian
09, revision A.01. Gaussian, Inc., Wallingford
34. Burgi H-B, Dunitz JD (1994) Structure correlation, vol 2. VCH,
Weinheim
35. Shishkin OV, Leszczynski J (1999) Chem Phys Lett 302:262
36. Shishkin OV, Gorb L, Leszczynski J (2009) Struct Chem 20:743
´
23. Furmanchuk A, Shishkin OV, Isayev O, Gorb L, Leszczynski J
(2010) Phys Chem Chem Phys 12:9945
24. Gordienko OV, Negrebetskii VV, Ivanchenko VI, Kornilov MY
(1989) Russ J Gen Chem 59:2771
25. Kornilov MY, Makovetsky VP (1974) Ukr Khim Zh 40:1175
37. Biitseva AV, Rudenko IV, Hordiyenko OV, Jamart-Gregoire B,
Arrault A (2012) Eur J Org Chem 2012:4387
38. Elvidge JA, Barot NR (1977) In: Patai S (ed), The chemistry of
functional groups part 2. imidines and diamidides (1,3,5-triaza-
pentadienes). Wiley, London
123