Structural Isomerization of 2-Anilinonicotinic Acid Leads to a New Synthon in 6-Anilinonicotinic Acids

Article abstract of DOI:10.1021/acs.cgd.8b00840

Through structural modification of 2-anilinonicotinic acid by isomerization, a new synthon, acid-aminopyridine, is created, and the two original synthons, i.e., the acid-acid homosynthon and acid-pyridine heterosynthon are no longer observed in the newly

Full text of DOI:10.1021/acs.cgd.8b00840

Communication
Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX
pubs.acs.org/crystal
Structural Isomerization of 2‑Anilinonicotinic Acid Leads to a New
Synthon in 6‑Anilinonicotinic Acids
†
†
†
‡
§
∥
Siqing Peng, Faquan Yu, Danrui Xu, Conggang Li, Sean R. Parkin, Tonglei Li,
,⊥
,†
Mingtao Zhang,* and Sihui Long*
†Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan
Institute of Technology, Wuhan, Hubei 430073, China
‡
Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China
§
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, United States
∥
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
⊥
Department of Chemistry, Nankai University, Tianjin, 300071, China
*
S Supporting Information
ABSTRACT: Through structural modification of 2-anilinoni-
cotinic acid by isomerization, a new synthon, acid-amino-
pyridine, is created, and the two original synthons, i.e., the
acid−acid homosynthon and acid−pyridine heterosynthon are
no longer observed in the newly designed 6-anilinonicotinic
acids. The new synthon has a hydrogen-bond strength rivaling
that of the acid−acid homosynthon and the acid−pyridine
heterosynthon, as suggested by theoretical calculations, which
explains its formation.
nilinonicotinic acids, particularly 2-anilinonicotinic acids
(2-ANAs), have been investigated as nonsteroidal anti-
In the aforementioned 2-ANA compounds, delocalization of
A
the lone pair electrons on the anilino N renders the C−N bond
inflammatory drugs (NSAIDs), and clonixin and flunixin are
(shown in 1a) partially double, which means the molecules can
1
−3
25−27
two representatives.
2-ANAs are conformationally flexible
have either E or Z configuration, theoretically.
In practice,
compounds with both carboxylic acid and pyridine groups, and
only the Z-isomer is observed in the diarylamine compounds
due to the formation of an intramolecular hydrogen bond
between NH and the carbonyl CO of the carboxylic
they are known to form crystals sustained either on the acid−
4
−8
acid or acid−pyridine hydrogen-bonding motifs.
When the
28−32
acid−acid dimer is observed, the molecules usually take a
near) coplanar conformation, and if the acid−pyridine
heterosynthon is formed, a twisted conformation (i.e., the
acid.
For the alkylated anilino diarylamines such as 2-
(
PPNA, the molecules are E-isomers instead, likely due to steric
33,34
hindrance.
4
−6,9
two aromatic rings are nonplanar) dominates.
Statistically,
2-ANAs are not the only compounds with both carboxylic
the acid−pyridine heterosynthon is preferred as it is energeti-
acid and pyridine functionalities. What would happen if the
structural variation is based on shifting the whole benzene ring
5
,10−13
cally favored.
Yet, for 2-anilinonicotinic acids, either
acid−acid or acid−pyridine synthon can be induced by crystal
engineering approaches. To wit, the acid−acid homosynthon
can be forced by installing highly electron-withdrawing groups
such as fluorine on the benzene ring, and the acid−pyridine
heterosynthon can be engineered either through introducing
bulky (steric hindering) groups at the 2 and/or 6 position of
the benzene ring or adding an alkyl group to the aniline N. In
addition, a polymorphic form of 2-(phenyl-propyl-amino)-
nicotinic acid (2-PPNA) was found to possess both the acid−
acid homosynthon and acid−pyridine heterosynthon and the
underlying mechanism was explored which demonstrates the
subtle interplay between conformation and intra/intermolec-
from position 2 of the pyridine ring to position 6, i.e.,
35−37
isomerization is utilized to modify the molecules?
These
new compounds, i.e., 6-anilinonicotinic acids (6-ANAs), have
not been investigated either in medicinal chemistry or in
crystal engineering. Structurally, they still possess partial
double bond property for the corresponding C−N bond
(
Figure 2a), which should again lead to E and Z configura-
tional isomers, and the intramolecular hydrogen bond between
Received: June 2, 2018
Revised: July 27, 2018
Published: August 3, 2018
14−24
ular interactions (Figure 1).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Figure 1. Acid−acid homosynthon (a), acid−pyridine heterosynthon
(b), and coexistence of both synthons in 2-PPNA (c).
Figure 3. Synthesis of six 6-ANAs.
NH and CO is no longer feasible. Will the acid−acid
homosynthon (2a) be preferred or the acid−pyridine
heterosynthon (2c) be favored, or will new synthons such as
the acid−aminopyridine (2d) and the aminopyridine−amino-
A preliminary polymorph screening was carried out for each
4
9−51
compound.
These compounds are not particularly soluble
in most common solvents used for crystal growth. For all the
compounds, one crystal form has been discovered so far. All
the crystals are colorless with various morphologies. The
crystal structures were determined by single-crystal X-ray
diffraction. Crystals of compound 4 were triclinic, space group
38−42
pyridine (2b) emerge in the newly designed 6-ANAs
Figure 2)? Investigation of 6-ANAs should shed light on the
(
relationship between the location of functional groups and/or
conformation and crystal packing (e.g., polymorphism) and
also contribute to the field of crystal structure prediction.
̅
P1, while all the other compounds gave orthorhombic crystals
43−46
with varying space groups. Crystallographic data are given in
Table 1. For complete CIF files, see the Supporting
Information. All the crystals have only one crystallographically
independent molecules (Z′ = 1) in each of the asymmetric
units except for that of compound 4, which has two
independent molecules (Z′ = 2). The benzene ring of the
molecule in compound 6 is disordered over two positions with
the major one having an occupancy of 92%. All molecules
In this study, we designed a series of 6-ANAs and
investigated the effect of isomerization on the crystal structure,
particularly on the synthon formation.
Six 6-ANAs were synthesized according to a similar
approach to the synthesis of 2-anilinonicotinic acid, i.e., the
47,48
SNAr reaction (Figure 3).
(the detailed procedure and
characterization are included in the Supporting Information)
Figure 2. Possible synthons in the 6-ANA crystals: a. acid−acid homosynthon, b. aminopyridine−aminopyridine homosynthon, c. acid−pyridine
heterosynthon, d. acid−aminopyridine heterosynthon.
B
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Table 1. Crystallographic Data of Compounds 1−6
1
2
3
4
5
6
formula
C H N O
C H N O
C H N O
C H N O
C H N O
C H F N O
2
1
2
10
2
2
13 12
2
2
15 16
2
2
14 14
2
2
15 16
2
2
12
8
2
2
formula weight
214.22
228.25
256.30
242.27
256.30
250.20
crystal size (mm)
0.15 × 0.15 × 0.03
orthorhombic
Pbca
13.8359(2)
7.1891(4)
20.9809(6)
90.00
90.00
90.00
8, 1
2086.92(13)
1.364
0.30 × 0.10 × 0.10
orthorhombic
Pbca
13.7049(3)
7.6401(2)
21.0500(5)
90.00
90.00
90.00
8, 1
2204.08(9)
1.376
0.50 × 0.40 × 0.05
orthorhombic
Pca21
28.3815(12)
5.3804(2)
8.5880(4)
90.00
90.00
90.00
4, 1
1311.42(10)
1.298
0.4 × 0.3 × 0.1
triclinic
0.30 × 0.20 × 0.05
orthorhombic
Pbca
6.47500(10)
13.6795(3)
29.3965(8)
90.00
90.00
90.00
8, 1
2603.79(10)
1.308
0.20 × 0.10 × 0.10
orthorhombic
Pca21
19.57220(10)
3.9750(4)
13.5879(6)
90.00
90.00
90.00
4, 1
1057.13(12)
1.572
crystal system
space group
a/Å
b/Å
c/Å
P1
̅
10.7437(4)
10.8657(4)
11.3689(5)
101.8235(16)
101.4872(17)
100.7778(16)
4, 2
α/°
β/°
γ/°
Z, Z′
V/Å3
1236.58(8)
1.301
D /g × cm−
3
cal
T/K
90(2)
0.095
896
90(2)
0.095
960
90(2)
0.087
544
90(2)
0.089
512
90(2)
0.088
1088
90(2)
0.133
512
abs coeff (mm−1)
F(000)
q range(deg)
1.94
1.93
1.43
1.89
2.77
2.56
2
3.81
27.45
27.47
27.23
27.50
27.45
limiting indices
−15 ≤ h ≤ 15
−9 ≤ h ≤ 9
−17 ≤ k ≤ 17
−27 ≤ l ≤ 27
100.0%
1689
0.0481
−36 ≤ h ≤ 36
−6 ≤ k ≤ 6
−11 ≤ l ≤ 11
99.8%
1795
0.0440
−13 ≤ h ≤ 13
−13 ≤ k ≤ 13
−14 ≤ l ≤ 14
99.1%
3803
0.0492
−8 ≤ h ≤ 8
−17 ≤ k ≤ 17
−37 ≤ l ≤ 38
99.9%
6248
0.0556
−24 ≤ h ≤ 24
−5 ≤ k ≤ 5
−17 ≤ l ≤ 17
100.0%
921
0.0519
−
−
8 ≤ k ≤ 8
23 ≤ l ≤ 23
completeness to 2θ
Unique reflections
R1[I > 2σ(I)]
100.0%
1891
0.0495
0.1420
wR (all data)
2
0.1375
0.1282
0.1385
0.1588
0.1481
compound 2: 42.22 (5)°; compound 3: 61.25 (10)°;
compound 4: A, 50.70(6)° and B, 50.57(6)°; compound 5:
6
1.19 (7)°; compound 6: 43.07 (14)°).
Conformational variability is readily apparent in a super-
position of all seven experimental conformations (Figure 4).
Neither the conventional acid−acid homosynthon nor the
acid−pyridine heterosynthon was observed in the crystal
structures. Instead, an intermolecular hydrogen bond between
the carboxylic acid of one molecule and the pyridine N and
amino NH of another molecule, namely an acid-aminopyridine
2
52−54
heterosynthon, was formed (R (8)
). In a sense, this new
2
synthon is an enhanced version of the previous acid−pyridine
heterosynthon, because in the acid−pyridine heterosynthon,
2
the sp C−H adjacent to the pyridine N also hydrogen bonds
with the carbonyl O of the carboxylic acid.
Aside from compound 4, the aforementioned twisted
molecules form one-dimensional chains based on the acid-
aminopyridine heterosynthon (Figures 5−9), with varying
hydrogen bond parameters (Table 2).
Figure 4. Superposition of seven crystallographically independent
molecules in the six crystal structures.
Table 2. Hydrogen Bond Parameters of OH···N and NH···O
in Five 6-ANA Compounds
In compound 4, the two molecules (I-A and I-B) in the
asymmetric unit have nearly identical dihedral angles of
5
0.70(6)° and 50.57(6)° between the two aromatic rings. The
1
2
3
5
6
molecules form one-dimensional chains sustained on a
heterogeneous hydrogen-bonded dimer (R (8)) between the
OH···N bond length
Å)
1.801
1.795
1.864
1.816
1.769
2
2
(
carboxylic acid of one conformer and the pyridine N and
secondary amine of the other conformer (Figure 10). The
hydrogen bond between the carboxylic acid OH of conformer
B and pyridine N of conformer A has a bond length of 1.815 Å
and bond angle of 169.32°; the corresponding hydrogen bond
between the carboxylic acid OH of conformer A and pyridine
N of conformer B has parameters of 1.840 Å and 171.34°.
Meanwhile, the hydrogen bond between the secondary NH of
conformer A and the carbonyl O of conformer B has
OH···N bond angle
deg)
167.91
2.018
168.86
2.092
175.38
1.912
174.12
1.944
168.32
1.981
(
NH···O bond length
Å)
(
NH···O bond angle
deg)
176.39
171.78
175.88
172.53
176.77
(
adopt the E configuration. The molecules have dihedral angles
in the range from 40° to 60° (compound 1: 45.14 (8)°;
C
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Figure 5. Crystal packing of compound 1. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
Figure 6. Crystal packing of compound 2. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
Figure 7. Crystal packing of compound 3. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
parameters of 2.019 Å and 169.88°, and the hydrogen bond
between the secondary NH of conformer B and the carbonyl O
of conformer A has almost identical parameters of 2.014 Å and
double bond property of C6−N7 (bond length 1.363 Å, while
a typical C−N single bond has a bond length of 1.47 Å, and
5
5
CN has a bond length of 1.29 Å ), there are two
configurational isomers of 1, named 1-Z and 1-E, as shown
in Figure 11. Single-molecule isomers of 1 and their hydrogen-
bonded dimers were optimized from various initial con-
1
70.03°.
Since the molecules in all six crystals take a twisted
conformation, we wondered about the energy difference
between planar and twisted conformations. To that end, we
considered compound 1 as an example. Due to the partial
5
6,57
58
formations at the B3LYP/6-311+G(d,p)
and m06-2x /
59
Def2QZVP level to identify possible stable conformations
D
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Figure 8. Crystal packing of compound 5. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
Figure 9. Crystal packing of compound 6. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
E
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Figure 10. Crystal packing of compound 4. For clarity, only intermolecular hydrogen bonds are shown (dotted line).
Figure 11. Structure of 1 from the crystal structure with atoms labeled (a); planar Z-isomer from optimization (b); nonplanar E-isomer from
optimization (c).
6
0
(
using Gaussian16, Gaussian, Inc., Wallingford, CT, USA).
between the H atom on the pyridine ring and the H atom on
the benzene ring. This twisted conformation has a torsion
angle of 44.6°, which is consistent with the torsion angle of
Frequency calculations were performed for all optimized
structures to identify energy minima (zero imaginary
frequency, except for the hypothetical Cs-symmetry restricted
E-isomer). Intermolecular interactions were then calculated
with the basis set superposition error (BSSE) considered by
the counterpoise method. Dispersion energies were evaluated
using Grimme’s DFT-D3 corrections with Becke−Johnson
45.1° found in the conformer of the X-ray structure. A planar
E-isomer with assumed Cs symmetry restriction gave an
imaginary vibration frequency 3.06 kcal/mol higher in energy
than that of the twisted 1-E. The 1-Z isomer is less than 1 kcal/
mol higher in energy than that of the twisted 1-E (0.63 or 0.72
kcal/mol of Gibbs free energy based on B3LYP/6-311+G(d,p)
level or m06-2x/Def2QZVP level, respectively). The similar
stability between 1-Z and 1-E indicates that both isomers could
exist in the crystal synthons.
6
1,62
damping.
The temperature (298.15 K) and zero-point
vibrational energies (ZPVE) were also considered. All
63−65
calculations were conducted on a Linux cluster
The optimized molecule of 1-Z gives a planar structure
owing to the delocalized conjugation of both the aromatic
rings and the lone pair electrons of the secondary amine N
atom. 1-E, however, is twisted because of the repulsion
We then examined the free energies of these different
possible synthons; their energies are listed in Table 3:
F
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Table 3. Calculated Free Energies of the Possible Synthons
C−H···O and O−H···N in II, O−H···N in III, and N−H···N in
IV. The calculated binding energies are −6.18 kcal/mol, −1.01
kcal/mol, −5.58 kcal/mol, and −3.01 kcal/mol, respectively.
The C−H···O hydrogen bond in II is much weaker than O−
H···O, N−H···N, and O−H···N, so the binding energy of II is
correspondingly lower than that of I, III, and IV, while I and III
show similar binding energies. The electronegativity of N in
pyridine is less than that of O in the carboxyl, which makes
carboxyl a better hydrogen bond acceptor, so the hydrogen
bonds in 1-EE-I and 1-EE-III are stronger than that in 1-EE-IV.
The corresponding free energies calculated at m06-2x/
Def2QZVP level in general agree with those from the
B3LYP/6-311+g(d,p) level with the only discrepancy observed
for 1-EE-IV, which deserves further investigation. Nevertheless,
the comparison holds only for the dimers. For types II and III
hydrogen bonding patterns, infinite chains are possible, which
should provide additional stability. For example, when we
consider four molecules, for type I dimer, two dimers will form,
while for types II and III, three dimers become feasible, which
should be more stable.
a
,
c
,
bc
synthon
BSSE (kcal/mol)
ΔG (kcal/mol)
ΔG (kcal/mol)
1
-EE-I
0.77
0.66
0.88
1.05
1.34
1.56
0.90
−6.18
−1.01
−5.58
−3.01
0.67
1.08
−5.62
−5.94
−0.05
−3.95
0.16
0.93
1.12
1-EE-II
1-EE-III
1-EE-IV
1-ZZ-II
1-ZZ-II*
1-EZ-III
−3.97
a
Energies calculated at B3LYP/6-311+g(d,p) level with Grimme’s
DFT-D3 correction with Becke−Johnson damping, BSSE correction,
zero-point vibrational energies (ZPVE), and thermal correction
b
considered. Energies calculated at m06-2x/Def2QZVP level by
single-point calculations with Grimme’s DFT-D3 correction consid-
ered. BSSE correction was omitted. Zero-point vibrational energies
and thermal correction come from the B3LYP/6-311+g(d,p) level.
c
The ΔG values are relative energies to their constituents, i.e.,
ΔG(EZ) = G(EZ) − G(E) − G(Z). A negative ΔG means the
synthon is energetically favored.
Four synthons 1-EE-I, 1-EE-II, 1-EE-III, and 1-EE-IV
formed by 1-E are shown in Figure 12. All four synthons are
ring dimers by different hydrogen bond types, O−H···O in I,
For Z-isomers of 1 to form a II-type synthon the molecule
must twist to a larger degree to make the pyridine N atom
accessible for hydrogen bonding; thus 1-ZZ-II and 1-ZZ-II*
Figure 12. Structure of the synthons of (a) 1-EE-I, (b) 1-EE-II, (c) 1-EE-III, and (d) 1-EE-IV.
G
DOI: 10.1021/acs.cgd.8b00840
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Communication
Figure 13. Structure of the synthons of 1-ZZ-II (a) and 1-ZZ-II* (b).
Figure 14. Structure of the synthons of 1-EZ-III.
(
Figure 13) were optimized with different twisted orientations.
isomer would have a binding energy of −5.62 kcal/mol, which
is similar to that of 1-EE-III or 1-EE-I. These data suggest that
likely the E/Z isomers compete with each other during the
process of synthon utilization.
Their binding energies, at 0.67 and 1.08 kcal/mol, respectively,
mean they are not thermodynamically favored. Moreover, a 1-
EZ-III (Figure 14) synthon formed by an E-isomer and a Z-
H
DOI: 10.1021/acs.cgd.8b00840
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Crystal Growth & Design
Communication
In all six structures, the EE-III type synthon is observed
which is in agreement with the stability analysis. Yet, the EZ-III
type synthon could be a good alternate given the opportunity.
Synthons play an important role in crystal engineering. New
synthons can be revealed either by chance or by design. In this
paper, a new synthon was created through structural
modification of 2-anilinonicotinic acids to 6-anilinonicotinic
acids. The new synthon has a similar hydrogen-bond strength
to that of the normally observed synthons in 2-anilinonicotinic
acids, i.e., acid−acid homosynthon and acid−pyridine
heterosynthon, which justifies its formation in the crystals.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.8b00840.
■
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AUTHOR INFORMATION
Corresponding Authors
Email: zhangmt@nankai.edu.cn.
E-mail: sihuilong@wit.edu.cn; longsihui@yahoo.com. Phone:
86) 15549487318.
ORCID
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Faquan Yu: 0000-0002-5062-8731
Conggang Li: 0000-0002-5798-1722
Tonglei Li: 0000-0003-2491-0263
Sihui Long: 0000-0002-4424-6374
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1
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(
S.P. and S.L. thank Natural Science Foundation of Hubei
Province (2014CFB787) and the President’s Fund of Wuhan
Institute of Technology (CX2016075) for financial support.
2
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