Unassisted formation of hemiaminal ether from 4-aminopyridine and o-vanillin - experimental and theoretical study

Article abstract of DOI:10.1007/s11224-018-1105-5

The reactions between o-vanillin and three isomeric aminopyridines lead to imines of diverse spatial conformation and reactivity. The direct products of these simple reactions carried out in methanol are either imine compounds formed in the reactions of 2

Full text of DOI:10.1007/s11224-018-1105-5

Structural Chemistry
https://doi.org/10.1007/s11224-018-1105-5
ORIGINAL RESEARCH
Unassisted formation of hemiaminal ether from 4-aminopyridine
and o-vanillin - experimental and theoretical study
A. Mielcarek1 & A. Wiśniewska1 & A. Dołęga1
Received: 15 November 2017 /Accepted: 21 March 2018
#
The Author(s) 2018
Abstract
The reactions between o-vanillin and three isomeric aminopyridines lead to imines of diverse spatial conformation and reactivity.
The direct products of these simple reactions carried out in methanol are either imine compounds formed in the reactions of 2-
amino- and 3-aminopyridine with o-vanillin or the α-aminoether formed in the reaction of o-vanillin with 4-aminopyridine. The
Schiff-type derivative of 4-aminopyridine and o-vanillin, which is described in this paper for the first time, is very reactive and
can only be obtained indirectly from the α-aminoether in anhydrous conditions. All compounds are characterized by X-ray
diffraction and FT-IR and NMR spectroscopies. The DFT calculations at all-electron BLYP/Q4ZP level of theory are utilized to
explain the differences between the reactivity of isomeric aminopyridines and their imine derivatives.
.
.
.
.
.
Keywords Aminopyridines α-Aminoether Imines XRD DFTcalculations RAHB resonance-assisted hydrogen bonds
Introduction
but quite counter-intuitively, the potencies of aminopyridines
seem to be unrelated to their pKa values which are determined
as 9.18 (4AP), 6.03 (3AP), and 6.71 (2AP) [19]. 4AP was also
proved to participate in the formation of very strong hydrogen
bonds, which is a rare case for nitrogen compounds [20, 21].
Quite recently, aminopyridine complexes with nitrophenol
were reported to possess good optical properties, thermal sta-
bility, and suitability for optoelectronic devices [22, 23].
The primary goal of our studies was to utilize the three
isomeric aminopyridines (APs) as precursors to a series of
imino compounds with the chelating or bridging properties
towards metal ions. We expected that the position of the pyri-
dine nitrogen with respect to the imine functionality within the
synthesized imines will allow to obtain metal complexes of
diverse character—either molecular or polymeric. We there-
fore repeated the known reactions between the 2- and 3-
aminopyridines and o-vanillin (OV) in methanol and applied
the same conditions for the reaction of 4-aminopyridine with o-
vanillin. As described previously, 2AP and 3AP reacted with
OV to produce typical Schiff compounds [24, 25]. However,
quite unexpectedly, the reaction between 4AP and OV that has
not been earlier reported in the literature led exclusively to
hemiaminal ether or undefined polymeric products. In the last
few years, direct formation of aminoethers was observed for
the reactions of pyridyl aldehydes and/or pyridylamines, but
these reactions were usually performed in the presence of metal
cations and the products were isolated as metal complexes
Aminopyridines (APs) have a variety of applications and po-
tential uses. Regarding chemical synthesis, they are important
building blocks in the synthesis of heterocyclic compounds
such as azaindoles and imidazopyridines [1]. They have been
applied as ligands or ligand precursors in metal-organic cata-
lytic systems [1–3], discrete or oligonuclear metal complexes,
metal clusters, and metal-organic frameworks (MOFs) [e.g.,
4–11]. In the field of medicine 4-aminopyridine (4AP), i.e.,
fampridine or dalfampridine (marketed as Fampyra® or
Ampyra®) is used in the treatment of multiple sclerosis (MS)
as it was shown to improve motor function of MS patients
[12–14]. This improvement is associated with the ability of
4AP and also other aminopyridines to block potassium chan-
nels [15–18]. It is usually presumed that the aminopyridines
exert their blocking activity in the protonated form [e.g., 16],
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11224-018-1105-5) contains supplementary
material, which is available to authorized users.
* A. Dołęga
anndoleg@pg.edu.pl
1
Department of Inorganic Chemistry, Chemical Faculty, Gdansk
University of Technology, Narutowicza 11/12,
80-233 Gdańsk, Poland

Struct Chem
[26–28]. Formation of hemiaminal ethers was also observed in
the presence of molecular sieves [29]. Quite recently, the for-
mation of stable hemiaminals was also described for the reac-
tions of substituted 4-amine-1,2,4-triazoles [30–32] and 2-
aminopyrimidine [33] with benzaldehydes.
In this paper, we report unassisted formation and isolation
of aminoether from 4AP and OV in methanol driven by a
particular reactivity of imine formed from OV and 4AP, and
we try to explain this special chemical behavior with the use of
DFT calculations. Complete crystallographic, FT-IR, and
NMR data for the isolated compounds are reported to illustrate
structural features and chemical behavior of the studied
compounds.
1H NMR (400 MHz) in DMSO-d6: 12.58 (bs, 1H, OH),
8.93 (s, 1H, C1H), 8.55 (dd, 0.8 Hz, 2.6 Hz, 1H, C13H), 8.42
(dd, 1.5 Hz, 4.7 Hz, 1H, C12H), 7.77 (ddd, 1.5 Hz, 3.6 Hz,
1H, C11H), 7.41 (ddd, 0.8 Hz, 4.3 Hz, 1H, C10H), 7.19 (dd,
1.5 Hz, 7.9 Hz, 1H, C8H), 7.08 (dd, 1.5 Hz, 8.0 Hz, 1H, C7H)
6.85 (t, 7.9 Hz, 1H, C6H), 3.75 (s, 3H, C5H3).
13C NMR (100 MHz) in DMSO-d6: 56.4 (C5), 116.4 (C7),
119.3 (C6), 119.8 (C3), 124.2 (C8), 124.6 (C10), 128.4 (C11),
143.9 (C13), 144.8 (C9), 148.2 (C12), 148.4 (C4), 150.8 (C2),
165.8 (C1).
2-Methoxy-6-(methoxy-4-pyridylaminomethyl)-phenol
3—after the reaction solution was concentrated to half volume.
Yellow plates of 3 crystalized after 1 day in 0 °C—as methanol
solvate, Mp. 56–67 °C. E.a. C15H19N2O4 (292.33): calcd. C
61.63, H 6.90, N 9.58; found C 61.72, H 7.18, N 9.65.
NMR spectra of 3 in DMSO-d6 indicate that in the solu-
tion, the prevailing form is imine 5, which is in agreement
with the orange color of the solution (crystals of compound
3 are very pale yellow).
Experimental
Synthetic procedures—general
Methanol, 2-hydroxy-3-methoxybenzaldehyde (o-vanillin,
OV), and aminopyridines (APs) were purchased from com-
mercial sources.
Compounds 1–4 were prepared by mixing metanolic solu-
tion (100 ml) of o-vanillin (6.08 g, 40 mmol) with equimolar
amount of 2AP, 3AP, or 4AP (3.76 g, 40 mmol) in methanol
(50 ml). The reaction mixtures were heated under reflux for
1 h and subjected to the procedures described below.
Compound 5 was obtained from compound 4 by the pro-
cedure described below.
1H NMR (400 MHz) in DMSO-d6: 12.42 (bs, 1H, OH),
9.04 (s, 1H, C1H), 8.67 (dd, 1.6 Hz, 4.5 Hz, 2H, C10H and
C13H), 7.42 (dd, 1.6 Hz, 4.5 Hz, 2H, C11H and C12H), 7.36
(dd, 1.5 Hz, 7.9 Hz, 1H, C8H), 7.24 (dd, 1.5 Hz, 8.0 Hz, 1H,
C7H), 7.00 (t, 7.9 Hz, 1H, C6H), 4.19 (bs, 2H, OH) 3.89 (s,
3H, C5H3), 3.23 (s, 6H, C14H3).
13C NMR (100 MHz) in DMSO-d6: 49.1 (C14), 56.4 (C5),
116.7 (C7), 116.8 (C11, C12), 119.4 (C6), 119.7 (C3), 124.1
(C8), 148.6 (C4), 150.9 (C2), 151.4 (C10, C13), 155.8 (C9),
166.6 (C1).
Copies of NMR spectra for 1–5 are provided as
Supplementary Materials. Observed FT-IR bands and their
assignments are found in Supplementary Materials as
Table 1S and Figs. 1S–5S.
2-Methoxy-6-(E-2-pyridyliminomethyl)-phenol 1, crys-
tallized after 1 day at room temperature as reddish orange
needles (4.77 g, 49.3%). Mp. 97–100 °C. E.a. C13H12N2O2
(228.25): calcd. C 68.41, H 5.30, N 12.27; found C 68.39, H
5.31, N 12.22.
2-Methoxy-6-(4-pyridyliminomethyl)-phenol
dihydrate? 4 was obtained in the form of red oil after re-
moval of methanol from the reaction mixture—first with the
use of vacuum rotary evaporator and then oil pump
(0.01 mmHg, 5 h) (8.82 g, 83.2%). The oil spontaneously
polymerized (or condensed) and in time turned into dark red
amorphous solid. Elemental analysis and FT-IR results
point to the presence of (C13H12N2O2)(H2O)2 in the oil
(264.28): calcd. C 59.08, H 6.10, N 10.60; found C 59.39,
H 6.34, N 9.83.
1H NMR (400 MHz) in DMSO-d6: 13.06 (bs, 1H, OH),
9.40 (s, 1H, C1H), 8.46 (ddd, 0.9 Hz, 2.2 Hz, 1H, C11H), 7.85
(ddd, 1.9 Hz, 5.1 Hz, 1H, C10H), 7.29 (dt, 1.0 Hz, 7.9 Hz, 1H,
C13H), 7.28 (ddd, 1.1 Hz, 4.1 Hz, 1H, C12H), 7.27 (dd,
0.3 Hz, 1.5 Hz, 1H, C8H), 7.09 (dd, 1.5 Hz, 8.2 Hz, 1H,
C7H), 6.84 (t, 7.9 Hz, 1H, C6H), 3.75 (s, 3H, C5H3).
13C NMR (100 MHz) in DMSO-d6: 55.4 (C5), 116.6 (C7),
119.3 (C6), 119.4 (C3), 120.1 (C13), 123.4 (C12), 124.9 (C8),
139.6 (C10), 148.5 (C4), 149.5 (C11), 151.7 (C2), 157.8 (C9),
165.0 (C1).
2-Methoxy-6-(Z-3-pyridyliminomethyl)-phenol 2, crys-
tallized as orange needles immediately after cooling of the
reaction mixture to room temperature (7.82 g, 79.5%). Mp.
120–125 °C. E.a. C13H12N2O2 (228.25): calcd. C 68.41, H
5.30, N 12.27; found C 68.39, H 5.24, N 12.30.
1H NMR (400 MHz) in DMSO-d6: 8.01 (m, 2H, C10H and
C13H), 6.51 (m, 2H, C11H and C12H), 3.89 (s, 3H, C5H3),
3.23 (s, 3H, OCH3) additionally very broad signals at
3.65 ppm and in the 5.5–8.0 ppm range.
13C NMR (100 MHz) in DMSO-d6: 49.1 (C14), 56.2 (C5),
109.3 (C11, C12), 149.6 (C10, C13), 154.9 (C9), 166.2 (C1).
2-Methoxy-6-(4-pyridyliminomethyl)-phenol 5 was ob-
tained in form of pale-orange-grayish powder by mild heating
of 1.00 g of 3 in Schlenk flask under reduced pressure of
argon (0.01 mmHg, 1 h). The yield at this stage ~ 100%,
E.a. C13H12N2O2 (228.25): calcd. C 68.41, H 5.30, N 12.27;
found C 68.39, H 5.24, N 12.30. The powder was recrystal-
lized from Na/K-dried toluene yielding colorless crystals of 5
(the yield of recrystallization ~ 50%).

Struct Chem
1H NMR (400 MHz) in DMSO-d6: 12.24 (bs, 1H, OH),
information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK. Fax: 44(1223)336–033, e-mail:deposit@ccdc.cam.ac.uk,
or www: www.ccdc.cam.ac.uk.
8.89 (s, 1H, C1H), 8.53 (dd, 1.6 Hz, 4.5 Hz, 2H, C10H and
C13H), 7.27 (dd, 1.6 Hz, 4.5 Hz, 2H, C11H and C12H), 7.22
(dd, 1.4 Hz, 7.9 Hz, 1H, C8H), 7.10 (dd, 1.4 Hz, 8.1 Hz, 1H,
C7H), 6.86 (t, 7.9 Hz, 1H, C6H), 3.75 (s, 3H, C5H3).
13C NMR (100 MHz) in DMSO-d6: 56.4 (C5), 116.7 (C7),
116.8 (C11, C12), 119.4 (C6), 119.7 (C3), 124.1 (C8), 148.5
(C4), 150.9 (C2), 151.4 (C10, C13), 155.8 (C9), 166.6 (C1).
Computational details
DFT calculations were performed using ADF program (ver.
2014.01) [40–42] with GGA BLYP XC potential and all-
electron QZ4P basis in SCF model as implemented in ADF
[43–46] in vacuum conditions. X-ray structures of 1, 2, and 5
were used as starting geometries yielding optimized structures
denoted 1, 2, and 5a. Optimized geometry of 5b (conformer of
5a) was obtained from the optimized geometry of 2 with the
changed position of nitrogen atom and subsequent optimiza-
tion. Hirshfeld surfaces [47] for both compounds were calcu-
lated using CrystalExplorer (version 3.1). [48]. Mayer bond
orders, dipole moments, and Bader charges were calculated
with the use of procedures implemented in ADF.
Physical measurements
Infrared transmission spectra of crystalline products were re-
corded using Nicolet iS50 FT-IR spectrometer equipped with
the Specac Quest single-reflection diamond attenuated total
reflectance (ATR) accessory. Spectral analysis was controlled
1
by the OMNIC software package. The H and 13C NMR
spectra were obtained in DMSO-d6 with a Bruker Avance
III HD 400 MHz spectrometer using standard pulse se-
quences. Solution electronic spectra were recorded on a
Unicam SP300 spectrometer. The elemental CHNS analyses
were performed on an Carlo Erba Elemental Analyzer EA
1108. The melting points of the compounds were determined
on an SMP3 apparatus (Stuart Scientific, UK).
Results and discussion
Syntheses
X-ray crystallography
Initially, we repeated the syntheses of two typical
benzylideneanilines from 2-AP, 3-AP, and o-vanillin: 2-
methoxy-6-(2-pyridyliminomethyl)-phenol 1 and 2-
methoxy-6-(3-pyridylimino-methyl)phenol 2 (Scheme 1).
Both compounds were reported earlier, but in the case of 1,
molecular structure was not determined [24] contrary to 2,
which was characterized exclusively by X-ray diffraction
[25]. We have replaced ethanol [as described in 24] by meth-
anol; however, this was not a matter of deliberate action—we
did not expect any differences in the course of reaction, and
indeed 2-AP and 3-AP reacted as described before.
The reaction between 4-aminopyridine and o-vanillin per-
formed in the comparable conditions instead of the expected
imine led to a different crystalline product—hemiaminal ether
3 (Scheme 1). Compound 3 was obviously the result of addi-
tion of methanol to the double bond of the imine present in the
methanolic solution of OVand 4-AP. The apparent conclusion
was supported by the orange color of the solution of OVand 4-
AP—whereas isolated crystalline compound 3 was pale yel-
low. NMR spectra of 3 in DMSO-d6 confirmed the presence
of imine bond in the solution (see BNMR spectroscopy^). We
decided to remove methanol from the solution of OV and 4-
AP to force the formation of imine. The solvent was removed
in vacuum conditions, and in this way, we obtained dark-
orange and viscous oil 4 that probably contained the imine
compound and water strongly connected to it as confirmed
by FT-IR spectra and the results of elemental analysis. We
were unable to determine the character of the imine–water
Single crystal X-ray diffraction data of compounds 1, 2, 3, and
5 were collected on a Stoe IPDS-2T diffractometer with
graphite-monochromated Mo-Kα radiation; crystals were
cooled using a Cryostream 800 open flow nitrogen cryostat
(Oxford Cryosystems). Data collection and image processing
were performed with X-Area 1.75 [34]. Intensity data were
scaled with LANA (part of X-Area) in order to minimize
differences of intensities of symmetry-equivalent reflections
(multi-scan method).
Structures were solved by direct methods, and all non-
hydrogen atoms were refined with anisotropic thermal param-
eters by full-matrix least squares procedure based on F2 using
the SHELX–2014 program package [35]. The Olex [36] and
Wingx [37] program suites were used to prepare the final
versions of cif files. Olex was also used to prepare the figures.
Hydrogen atoms were usually refined using isotropic model
with Uiso(H) values fixed to be 1.5 times Ueq of C atoms for –
CH3 or 1.2 times Ueq for –CH2 and –CH groups. Disordered
molecule of methanol present in the crystals of compound 3
was removed from the final solution using program PLATON,
function SQUEEZE [38]. Flack parameter was calculated as
described in [39]. Crystal parameters and refinement details
are collected in Table 1.
Crystallographic data for the structural analysis has been
deposited with the Cambridge Crystallographic Data Center,
Nos. CCDC 1536273 (1), CCDC 1536274 (2), CCDC
1536275 (3), and CCDC 1546514 (5). Copies of this

Struct Chem
Table 1 Crystal data and structure refinement for the (1, 2, 3, and 5)
1
2
3
5
Chemical formula
C13H12N2O2
228.25
C13H12N2O2
C14H16N2O3
C13H12N2O2
228.25
Mr
228.25
260.29
Crystal system,
space group
a, b, c (Å)
Monoclinic, P21/n
Orthorhombic, P212121
Orthorhombic, P212121
Orthorhombic, Pbca
12.289(7),
4.9356(16),
18.401(10)
5.5401(5),
9.2005(11),
21.6097(18)
9.720(4),
9.818(6),
16.310(9)
6.8565(19),
17.698(3),
18.472(5)
α, β, γ (°)
V (Å3)
90, 102.19(5), 90
1091.0(10)
90, 90, 90
90, 90, 90
90, 90, 90
1101.48(19)
0.10
1556.5(14)
2241.5(9)
μ (mm−1
)
0.10
0.08
0.09
Crystal size (mm)
0.51 × 0.22 × 0.07
4788, 2063, 1480
0.54 × 0.42 × 0.34
8359, 2157, 1946
0.57 × 0.32 × 0.17
7162, 3013, 2643
0.08 × 0.07 × 0.06
14,742, 2216, 1386
No. of measured,
independent and
observed [I > 2σ(I)]
reflections
Rint
0.085
0.049
0.126
0.97
0.042
0.031
0.077
1.02
0.045
0.076
0.202
1.06
0.088
0.052
0.138
1.02
R[F2 > 2σ(F2)]
ωR(F2)
S
No. of reflections
2063
158
215
3013
2216
158
No. of parameters
159
183
Δρmax, Δρmin (e Å−3
)
0.21, − 0.28
–
0.15, − 0.22
0.51, − 0.27
0.19, − 0.26
–
Absolute structure
Flack × determined
using 746 quotients
[(I+)−(I−)]/[(I+) + (I−)]
0.0 (7)
Flack × determined
using 973 quotients
[(I+)−(I−)]/[(I+) + (I−)
− 0.1 (9)
Absolute structure
parameter
–
–
complex 4 experimentally. In time, the oil solidified, which
indicated further polycondensation or polymerization of the
imine. Out of common laboratory solvents, compound 4 was
soluble only in DMSO and the NMR spectra of this solution
indicated complicated equilibrium mixture. The NMR spectra
of all compounds are presented in Supplementary Materials.
Finally, we synthesized the desired imine compound 5 by
the removal of methanol from the solid 3 in vacuum condi-
tions. In this way, we obtained yellowish-gray powder that
was recrystallized from toluene dried over Na/K to avoid ad-
dition of water to the newly formed imine bond. The results of
elemental analysis and NMR spectroscopy suggested that we
obtained pure imine and the molecular structure determined
with the use of X-ray diffraction for the colorless (!) crystals
confirmed the first-time isolation of 2-methoxy-6-(4-pyridyl-
iminomethyl)phenol, 5. Without the protective argon or nitro-
gen atmosphere, this reactive compound quickly decomposes.
Interestingly, the reaction between the OV and 4AP in
ethanol has not been mentioned in the literature so far. We
performed the reaction in ethanol, but unlike in the reaction
carried out in methanol, we did not obtain crystalline prod-
uct—neither imine nor aminoether. However, the respective
imine probably formed in solution as proved by the change
in the color of the solution. We further analyze the reactions
Scheme 1 The formulas and symbols of the obtained compounds

Struct Chem
in MeOH, EtOH, and DMSO in the chapter devoted to the
description of UV-Vis spectra of the compounds.
The formulas of compounds 1–3 and 5 are presented in
Scheme 1.
Crystal structures
Crystal parameters and refinement details are collected in
Table 1. Molecular structures of imines 1, 2, and 5 are overlayed
in Fig. 1 and additionally presented as Fig. 6Sa–c of
Supplementary Materials. Molecular structure of aminoether 3
is shown in Fig. 2. Bond lengths in 1, 2, 3, and 5 are collected in
Table 2S.
Fig. 2 Molecular structure of compound 3. Thermal ellipsoids at 50%
probability level
Compounds 1 and 5 crystallized in centrosymmetric
groups (P21/n and Pbca, respectively), whereas compounds
2 and 3 crystallized in the non-centrosymmetric group
P212121. The forms of the crystals are correlated with the unit
cell parameters (a, b, c) for compounds 1, 2, and 3. Compound
3, which crystallized with similar a and b parameters, forms
plates but 1 and 2, in which b parameter is more than 1.5 times
larger than a, crystallize as needles. Compound 5 forms irreg-
ular crystals. The crystal structure of 2 is a low-temperature
redetermination of data described previously [25]. The crystal
system, in which the compound 2 crystallized, did not change
in the low temperature of the measurement, but size of the unit
cell was reduced along with the decrease of bond lengths and
intermolecular distances, typical of low temperature measure-
ments (Table 1) [49].
The length of azomethine bond is similar for two Schiff
bases: 1.287(3) Å in 1 and 1.286(3) Å in 2. This bond is
shorter by ca. 0.1 Å for compound 5 (1.276(3) Å). It is ob-
served that along with the migration of nitrogen within the
pyridyl substituent, the molecules of imines 1, 2, and 5 be-
come non-planar, which is caused by rotation of the
aminopyridine ring about the imine C1-N1 bond with respect
to the plane of the vanillin residue. The angle of rotation is 6°,
31.5°, and 74° in 1, 2, and 5, respectively (Fig. 1).
this is not the only reason since in our series, the steric inter-
ference in 2 and 5 is similar, yet the degree of rotation is very
different.
Due to the large twist in 5, the π systems of aromatic rings
are no longer conjugated via the imine bond, and consequent-
ly, the crystals of 5 are colorless, whereas 1 and 2 are orange.
The molecular structures of Schiff compounds 1 and 2
were solved as enol-imine tautomers, as concluded from their
short C1 = N1 (1.276(3)–1.287(3) Å) and relatively long C3-
O1 (1.348(3) and 1.353(2) Å) bonds. The relevant distance
Car-O in keto-amine tautomers is approx. 1.29 Å as analyzed
in ref. [51]. Because of the peculiar arrangement of atoms in 5,
formation of keto-amine tautomer is not possible.
The C-N bond in α-aminoether 3 has length of 1.408(6) Å,
which is obviously a distance of a single bond, and aromatic
rings are nearly perpendicularly oriented (86°) as in 5.
Both 2-amino- and 3-aminopyridine rings may condensate
with o-vanillin to two different isomers: Z and E. As a result of
the reactions, we obtained E isomer of 1 and Z isomer of 2.
Compound 3, which has a chirality center at C1 crystallized as
R enantiomer.
All compounds form hydrogen bonds. The illustrations and
geometrical parameters of hydrogen bonds are presented in
Fig. 3 and in the Supporting information as Figs. 6Sa, 6Sb,
7S, and 8S and Table 3S. There are intramolecular hydrogen
bonds O-H···N=C in structures of compounds 1 and 2 indicat-
ed as dashed lines in Fig. 6Sa, b. These intramolecular hydro-
gen bonds do not occur in structures 3 and 5, which is an
important factor regarding the increased reactivity of imine 5
as will be discussed later. In crystals of 3 and 5, the intramo-
lecular hydrogen bonds are replaced by intermolecular inter-
actions. Both compounds feature hydrogen bonds between
hydroxyl group of o-vanillin ring and heterocyclic nitrogen
atom of the adjacent molecule (red spot in Fig. 3c, d,
Fig. 7S). In this way, in crystals of 3 and 5 1D hydrogen-
bonded chains are formed that are absent in 1 and 2. It is worth
to recall the fact that pyridine nitrogen of 4AP is the best
acceptor of proton among the three isomeric APs with pKa
In a series of similar compounds, the driving force for this
distortion was previously ascribed to steric interference be-
tween the ortho-hydrogen of the aniline ring and the hydrogen
of the Schiff-base linkage [50]. However, we point out that
Fig. 1 Overlay of molecular structures of compounds: 1 (red), 2 (blue),
and 5 (gray). Thermal ellipsoids at 30% probability level. Hydrogen
atoms removed

Struct Chem
Fig. 3 Hirshfeld surfaces of a
compound 1, b compound 2, c
compound 3, and d compound 5.
Red color: normalized contact
distances dnorm shorter than the
sum of van der Waals radii (1
d
norm = − 0.157, 2 dnorm = −
0.171, 3 dnorm = − 0.328, 5
norm = − 0.725), white color: van
der Waals contacts (1 dnorm
d
=
0.413, 2 dnorm = 0.418, 3 dnorm
0.789, 5 dnorm = 0.442), blue
color: normalized contact
=
distances exceeding the sum of
van der Waals radii (1 dnorm
=
1.048, 2 dnorm = 1.071, 3 dnorm
2.740, 5 dnorm = 1.125). (Color
figure online)
=
values equal 9.18, 6.03, and 6.71 for 4AP, 3AP, and 2AP,
respectively [19]. The intermolecular interactions in crystals
of 1 and 2 include weaker C-H···O between aromatic C-H
hydrogen atoms of one molecule and oxygen atoms of hy-
droxyl (in 1) or methoxyl (in 2) groups of the other molecule
(red spots in Fig. 3a, b).
Additionally, neighboring imine molecules 1, 2, and 5 in-
teract by π···π and C-H···π contacts as illustrated in Fig. 8S. In
1 aromatic pirydyl rings interact with imine bonds creating
tile-like structure in crystallographic bc plane (Fig. 8Sa). In
crystals of imine 2, C6-H6···π interactions form a layer paral-
lel to ac plane (Fig. 8Sb). Adjacent layers of molecules of
compound 5 are connected by C-H···π interactions (Fig. 8Sc).
The crystal packings strongly influence the FT-IR spectra
discussed in the next chapter.
Stretching vibration of O-H is not visible in the FT-IR
spectra of both the substrate (o-vanillin) and 1 and 2, which
is often the case for hydroxyl groups that participate in the
formation of intramolecular hydrogen bonds (Figs. 1S and
2S) [53, 54]. The νO-H modes present in the spectra of 3 and
4 in the range are due to the presence of methanol in crystals of
3 or water molecules in 4.
There are very broad bands 2800–2400 cm−1 in the spectra
of 3 and 5 (Figs. 3S and 5S) that indicate the delocalization of
phenolic protons between the phenol OH and pyridine nitro-
gen of the adjacent molecule. Such an effect is often connect-
ed with the formation of hydrogen-bonded chains as described
in the literature [55–57]; the 1-D HB chains formed by 3 and 5
are illustrated in Fig. 7S.
FT-IR bands observed for 1–5 and their assignments sup-
ported by DFT calculations are found in Supplementary
Materials as Table 1S and Figs 1S–5S.
FT-IR spectroscopy
NMR spectroscopy
FT-IR spectra of Schiff bases 1, 2, and 5 and α-aminoether 3
showed medium to strong bands in the range 1607–1639 cm−1
which are specific for azomethine >C=N bonds and pyridyl
rings [52]. These bands are red-shifted compared to the char-
acteristic bands present in parental aminopyridines shown in
Fig. 4. The AP bands located at 1621–1645 cm−1 originate
from stretching of C-NH2 bond which is no longer present in
their derivatives 1–5. Band of stretching mode of carbon-
oxygen bond (νC-O) is observed in the spectra of all obtained
compounds in the region 1265–1294 cm−1. The same band is
localized at 1249 cm−1 in o-vanillin spectra.
1
The analysis of H NMR, 13C NMR as well as HMBC and
HMQC NMR spectra of 1, 2, 3, and 5 dissolved in DMSO-d6
allowed the unambiguous assignment of all proton and carbon
signals.
The results of NMR experiments prove that in the solution,
the solid state structures of imines 1, 2, and 5 are basically
1
preserved. Characteristic H NMR shifts of phenol group at
13.06 ppm (compound 1), 12.58 ppm (2), and 12.24 (5) and
these of C1 carbon of the imine bond at 9.40 ppm (1), 8.93 ppm
(2), and 8.89 (5) confirm the presence of enol/imine

Struct Chem
Fig. 4 FT-IR spectra of aminopyridines and compounds 1, 2, 3, and 5
form of the compounds in solution. The difference in color
between the solid state (colorless) and solutions (orange) in
the case of 5 indicates the change of the angle between the
aromatic rings that allows their conjugation in solution.
Aminoether 3 when dissolved in DMSO-d6 begins to con-
vert into imine 5. It is obvious both from the orange color of
the solution and NMR signals, which are very similar to the
pattern detected for 1, 2, and 5 (Table 2).
Table 2 NMR assignments for 1, 2, 3, and 5 in DMSO-d6
Compound 1
H (ppm)
Compound 2
H (ppm)
Compound 3
H (ppm)
Compound 5
H (ppm)
δ
δC (ppm)
δ
δC (ppm)
δ
δC (ppm)
δ
δC (ppm)
C1H
C2
9.40
165.0
151.7
119.4
148.5
55.4
8.93
165.8
150.8
119.8
148.4
56.4
9.04
166.6
150.9
119.7
148.6
56.4
8.89
166.6
150.9
119.7
148.5
56.4
C3
C4
C5H3
C6H
C7H
C8H
C9
3.75
6.84
7.09
7.27
3.75
6.85
7.08
7.19
3.89
7.00
7.24
7.36
3.75
6.86
7.10
7.22
119.3
116.6
124.9
157.8
139.6
149.5
123.4
120.1
119.3
116.4
124.2
144.8
124.6
128.4
148.2
143.9
119.4
116.7
124.1
155.8
151.4
116.8
116.8
151.4
49.1
119.4
116.7
124.1
155.8
151.4
116.8
116.8
151.4
C10H
C11H
C12H
C13H
C14H3
O1H
OHCH3OH
7.85
8.46
7.28
7.29
7.41
7.77
8.42
8.55
8.67
7.42
7.42
8.67
3.23
12.42
4.19
8.53
7.27
7.27
8.53
13.06
12.58
12.24

Struct Chem
Fig. 5 UV-Vis spectra of compounds 1, 2, and 3 in methanol (left side of
the figure) and UV-Vis spectra of compound 3 in various solvents
(right side of the figure). The solvents were methanol, DMSO, and
ethanol—10 min after dissolution of 3 in EtOH (1) and several hours later
(2). Analytical concentration of 1, 2, and 3 was 1 × 10−4 mol dm−3
The 1H NMR spectrum of 3 features additional broad sig-
nal of OH group at 4.19 ppm (2H) and CH3 group at
3.23 ppm.
(6H)—both originating from the presence of methanol in
the solution. No coupling of OC14H3 with the C1 carbon was
observed in 2D HMBC, whereas 2D COSY shows correlation
only between OC14H3 and the OHCH3OH proton indicative of
the exclusive presence of Bfree^ methanol in the solution. The
integration of signals confirms the conclusion.
The NMR spectra of the oil 4 remaining after the removal
of methanol from the mixture of OV and 4-AP are not that
unambiguous. Signals are very broad showing the dynamic
character of the studied system. The oil dissolves only in
DMSO; therefore, low-temperature studies were not possible.
We think that 3 is partially polymerized or condensed imine or
aminoalcohol resulting from the addition of water to the imine
bond. All NMR spectra are presented in the Supplementary
Materials.
302 nm. The spectrum of 3 in methanol features an entirely
new band at 252 nm, the band at 280 nm is less intense, and
the band at ~ 300 nm is now a poorly resolved shoulder. It can
be concluded, both from the presented comparison and the X-
ray experimental data, that for 1, the imine is a dominating
form in methanolic solution, whereas in the case of 3, imine is
a minor component of the equilibrium mixture. Interestingly
in the UV-Vis spectrum of 2, the ratio of the intensities of
bands at ~ 302 and 280 nm is changed compared to the spec-
trum of 1, but we do not observe the formation of the new
band (252 nm) associated with the presence of aminoether.
We also measured the spectra of 3 in MeOH, in DMSO and
in EtOH. In our opinion, the spectra in solvents other than
MeOH indicate the formation of imine 5 and its subsequent
decomposition (Fig. 5, right side). In methanol, the equilibri-
um is shifted towards the formation of aminoether and this
prevents further transformations of the reactive imine 5.
DFT calculations
UV-vis spectroscopy
DFT calculations were performed to explain the facilitated
addition of methanol to the imine bond of 4-aminopyridine
derivative 5. We sought for the differences in Gibbs free en-
ergies of formation (ΔGf), Mayer bond orders (MBO), dipole
moments, Bader charges, and energies of frontier orbitals of
Schiff bases 1, 2, and 5 and their keto-amine tautomers: oxo1,
oxo2, and oxo5b (viz. Scheme 2). In the case of compound 5,
we performed the optimization both for the conformation that
The UV-Vis spectra of 1, 2, and 3 are shown in Fig. 5. In the
UV-Vis spectrum of 1 in methanol, the major band is observed
at λmax = 312 nm with two shoulders at 351 and 280 nm. In the
spectrum of methanolic solution of 2, this major band is slight-
ly shifted towards lower wavelengths (~ 302 nm) and the
shoulder band, which was observed in 1 at 280 nm that is
now at 284 nm and has an intensity equal to the band at
Scheme 2 Tautomeric forms of 1
(oxo1), 2 (oxo2), and 5b (oxo5b).
Numbering in pyridyl ring as in
Scheme 2

Struct Chem
Table 3 Calculated Gibbs free energies Gf and standard free energies of formation ΔGf of the obtained compounds 1, 2, 3, and 5 and their respective
keto-amino forms oxo1, oxo2, and oxo5b. ΔG of 1, 2, 5a, and 5b calculated from Eq. 1. DFT calculations at GGA-BLYP/QZ4P level of theory
1
oxo1
2
oxo2
3
5aa
5bb
oxo5b
Gf (kcal mol−1
ΔGf (kcal mol−1
)
− 4061.07
− 1.02
− 4061.16
− 1.11
− 4056.99
− 2.95
− 4053.49
+ 0.55
− 4696.39
− 4053.96
+ 2.66
− 4057.9
− 1.28
− 4053.49
+ 3.13
)
+ 12.52c
+16.46d
+15.18e
a Optimized crystal structure
b Optimized structure of 2 with the atom of nitrogen in pyridyl ring shifted to position 4
c ΔG = Gf3 − (Gf5a + GfMeOH)
d ΔG = Gf3 − (Gf5b + GfMeOH)
e ΔG = (Gf3 + GfH2O) − (Gf4AP + GfOV + GfMeOH)
was found in the crystal structure, which is denoted by 5a and
for the conformation similar to 1 and 2 that is likely to exist in
the solution, which is denoted by 5b (Scheme 2).
The values of ΔG of formation of Schiff bases in both
tautomeric forms collected in Table 3 were calculated as dif-
ferences between sum of free energies of the products and sum
of free energies of the substrates via Eq. 1:
between the free energies of 5a and 5b must be attributed to the
absence of intramolecular hydrogen bond in 5a—we clearly
observe that the formation of this intramolecular interaction de-
termines whether the reaction is spontaneous or not. In other
words, the formation of intramolecular HB is an important factor
(driving force) of the formation of imine. Yet, at the same time,
we know that the intramolecular HB in 5b must be relatively
easily broken and replaced by the intermolecular interactions as
indicated by the crystal structure of 5. On the basis of compar-
ison of Gf values for 5a and 5b, the energy of intramolecular
hydrogen bond in 5b can be estimated as 3.94 kcal mol−1.
The free energy of formation of aminoether is always pos-
itive—obviously less positive if the reaction does not require
breaking of the intramolecular hydrogen bond (HB), i.e.:
ΔGf ¼ ΣGproducts−ΣGsubstrates
ð1Þ
The detailed values of energies, free energies, and their
components (including ZPEs), for all substances participating
in the reactions, can be found in Supplementary Materials as
Table 4S.
For the formation of imines, the following equations were
considered:
5a þ MeOH→3 ΔGf ¼ þ 12:52 kcal mol−1
5b þ MeOH→3 ΔGf ¼ þ 16:46 kcal mol−1
ð6Þ
ð7Þ
OV þ 2AP→1 þ H2O ΔGf ¼ −1:02 kcal mol−1
OV þ 3AP→2 þ H2O ΔGf ¼ − 2:95 kcal mol−1
OV þ 4AP→5a þ H2O ΔGf ¼ þ 2:66 kcal mol−1
OV þ 4AP→5b þ H2O ΔGf ¼ − 1:28 kcal mol−1
ð2Þ
ð3Þ
ð4Þ
ð5Þ
Another important observation is connected with the free
energies of keto-amino tautomers oxo1, oxo2, and oxo5b. We
found out that with the migration of nitrogen in pyridyl ring,
the energies of these tautomers increase, and only for imine 1,
the energies of both tautomeric forms enol/imino and keto/
amino are comparable. This discovery, together with the pre-
vious experimental observations, indicates that imine 1 is sta-
bilized by the resonance-assisted hydrogen bond (RAHB),
whereas imine 5 is not, or at least not as well stabilized. The
keto-imino form oxo5b is substantially higher in energy (+
4.41 kcal mol−1) with regard to enol/imino form 5b. This is
probably the most important factor underlying the increased
Regarding the values of ΔGf, compound 2 is the most
thermodynamically stable imine (ΔGf = − 2.95 kcal mol−1);
however, taking into account the absolute values of energies
(Table 3), we see that out of three isomers 1, 2, and 5a/5b, the
energy and free energy of 1 is the lowest.
Comparing ΔGf of Schiff bases 5a and 5b, we find that the
first value is positive and second one is negative. The difference
Table 4 Calculated Mayer bond orders (MBO) of C1-N1 bond and magnitudes of dipole moments in compounds 1, 2, 3, and 5 (as 5a and 5b) and their
keto-amino tautomers oxo1, oxo2, and oxo5b. DFT calculations at GGA-BLYP/QZ4P level of theory
1
oxo1
2
oxo2
5a
5b
oxo5b
3
MBO of C1-N1 bond
Dipole moment [D]
1.832
0.369
1.391
1.713
1.823
4.253
1.412
4.089
1.827
7.383
1.815
4.385
1.391
3.307
0.927
7.759

Struct Chem
Table 5 Selected calculated
Bader charges in compounds 1, 2,
3, and 5 (as 5a and 5b) and their
keto-amino tautomers oxo1,
oxo2, and oxo5. DFTcalculations
at GGA-BLYP/QZ4P level of
theory
1
oxo1
2
oxo2
5a
5b
oxo5
3
N1imine
C1imine
Δq
− 1.064
0.569
− 1.092
0.472
− 1.068
0.580
− 1.090
0.478
− 1.033
0.619
− 1.070
0.581
− 1.092
0.475
− 0.996
0.790
1.633
1.564
1.648
1.568
1.652
1.651
1.567
1.786
N2Py
− 1.005
− 1.046
− 0.983
− 1.002
− 1.064
− 0.982
− 0.993
− 1.040
− 0.980
− 0.992
− 1.060
− 0.986
− 0.986
− 1.026
− 1.011
− 0.983
− 1.041
− 0.979
− 0.982
− 1.058
− 0.981
− 0.995
− 1.026
− 1.016
O1OH
O2OCH3
reactivity of 5. In 1, and less in 2, for which the energy of keto-
amino (oxo) form is intermediate, the formation of RAHB
strengthens the intramolecular HB and protects the imine bond
against the attack of nucleophile. The reactivities of three iso-
meric aminopyridines illustrate very well the importance and
influence of weak interactions onto the reaction course as de-
scribed before for many other systems [e.g., 58–61].
The above thesis is further supported by X-ray geometrical
parameters of hydrogen bonds—the shortest HB in found 1
(Table 3S). Moreover, the results of FT-IR also indicate the
delocalization of proton engaged in the formation of intramo-
lecular HB in 1 and 2 since the νOH mode is not visible in the
FT-IR spectra of these compounds (Figs. 1S and 2S).
More information about the studied molecules is provided
by the their (calculated) properties such as dipole moments
and Bader charges. These properties are collected in
Tables 4 and 5. The most important feature with regard to
the reactivity is the dipole moment, which is largest for 5 both
as 5a and 5b. Moreover, the twist of the rings that converts
conformer 5b into 5a generates a large increase in the dipole
moment—from 4.38 to 7.38. The difference in the polarity of
the molecules is especially large between 1 and the remaining
two isomers—please refer to Fig. 9S illustrating the vectors of
dipole moments of 1, 2, 5a, and 5b.
oxo5b are comparable. Values lower than 2 suggest that elec-
trons are delocalized into conjugated aromatic systems of the
substituents. Likewise, electron delocalization explains bond
orders of C1-N1 bond in keto-amino forms; they are close to
1.4 instead of 1. No substantial discrepancies between the iso-
mers are observed. The bond order of C1-N1 in α-aminoether
is less than 1 indicating a weak character of this covalent bond.
Nucleophilic addition of methanol to the imine bond be-
gins with the attack of methanol oxygen at the positively
charged atom of carbon C1 within the imine bond.
Calculations show that imine carbon C1 in 5, regardless the
form 5a or 5b, bears the highest positive Bader charge. The
differences between the Bader charges of imine carbon
(C1imine) and nitrogen (N1imine) denoted as Δq are similar
(1.633–1.652) for the investigated imines—a slight increase
in polarity of C1-N1 is observed for the following sequence: 1
< 2 < 5b < 5a (Table 5).
Finally, we analyzed the energies of frontier orbitals in 1, 2,
5a, and 5b, which are illustrated in Fig. 6. Orbital HOMO in
5a and 5b is stabilized compared to 1 and 2. At the same time,
LUMO in 5a is a high energy orbital in comparison to LUMO
in 1 or 2 and HOMO-LUMO separation in 5a is the largest
among the examined imines—in accordance with its color or
rather lack of color. It means that the form of 5 found in
crystals, i.e., 5a, is not expected to exhibit increased reactivity
towards nucleophilic addition of methanol, which is a hard
The calculated Mayer bond orders of C1-N1 bonds in 1, 2,
3, 5a, and 5b and their tautomeric forms oxo1, oxo2, and
Fig. 6 Energies and shapes of
HOMO and LUMO orbitals in
imines 1, 2, and 5 as 5a or 5b

Struct Chem
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Summary and conclusions
The reactions of o-vanillin with isomeric aminopyridines (APs)
lead to imines of diverse spatial arrangement of atoms and dis-
tinct reactivity. Whereas derivatives of 2AP and 3AP are isolable,
crystalline compounds, imine obtained from 4AP immediately
enters the subsequent reactions such as addition of nucleophile to
the imine bond or polymerization/condensation. The isolation of
this imine requires anhydrous conditions and has not been
achieved before. Moreover, the conformer present in solution is
different from the conformer that crystallizes. As shown by DFT
calculations, the increased reactivity of the imine derived from
OV and 4AP can be explained by the increased polarity of the
imine bond and most importantly by the destabilization of intra-
molecular resonance-assisted hydrogen bond (RAHB), which
protects the remaining isomers against the attack of nucleophiles.
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Compliance with ethical standards
Ethical statement All ethical guidelines have been adhered.
Conflict of interest The authors declare that they have no conflict of
interest.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made.
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