Enantiopure Schiff bases of amino acid phenylhydrazides: Impact of the hydrazide function on their structures and properties

Article abstract of DOI:10.1039/c7nj04597b

A rapid and eco-friendly synthesis of new enantiopure Schiff bases 5a-e was performed from various α-amino acid phenylhydrazides and 2-hydroxynaphthaldehyde using microwave or ultrasound irradiation in yields ranging from 57 to 75%. These imines were char

Full text of DOI:10.1039/c7nj04597b

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: N. Bouzayani, S.
MARQUE, B. Djelassi, Y. Kacem, J. Marrot and B. Ben Hassine, New J. Chem., 2018, DOI:
1
0.1039/C7NJ04597B.
Volume 40 Number
1
January 2016 Pages 1–846
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Page 1 of 11
Pl Ne ae swe Jd oo u nr no at l ao dfj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04597B
NJC
PAPER
Enantiopure Schiff bases of aminoacid phenylhydrazides: impact
of the hydrazide function on their structure and properties
Received 00th November 2017,
Accepted 00th January 20xx
a
b*
c
a*
b
Nadia Bouzayani, Sylvain Marque, Brahim Djelassi, Yakdhane Kacem, Jérôme Marrot and
a
Béchir Ben Hassine
DOI: 10.1039/x0xx00000x
A rapid and eco-friendly synthesis of new enantiopure Schiff bases 5a-e was performed from various α-
www.rsc.org/
amino acid phenylhydrazides and 2-hydroxynaphthaldehyde using microwave or ultrasound irradiation in
1
13
yields ranging from 57 to 75%. These imines were characterized using H & C NMR, FTIR, mass and UV-vis
spectroscopies. In addition, the solid state molecular structure of 5b was determined by single crystal X-ray
diffraction which shows that this compound adopts the zwitterionic form, crystallizing in the non-
1 1 1
centrosymmetric orthorhombic system with the space group P2 2 2 . DFT calculations show that the
BMK/6-31G(2df,2pd) method in the gas phase is well adapted to describe the geometry of the solid
state. Theoretical results corroborate the ionic character of this species in concordance with
spectroscopic results and lead to a new thin description. The Schiff bases 5a-e behave as organic
semiconductors with the Eog ≈ 2.77 eV. The in-vitro antibacterial study showed that these molecules
exhibited various levels of antibacterial effect against all the tested bacterial strains.
2
2
supplementary functions which favors a species in regard to
1
Schiff bases have been studied due to their significant
. Introduction
1
2
3
19
another, or else of the physical state , the solvent or the
2
temperature (Table 1). The work-up revealed sometimes
5
2
-6
properties in various fields . During the last years, they have
received great attention from scientists worldwide due to their
ease of synthesis, as precursors for the preparation of
2
6
crucial to isolate the compounds even in the solid state
.
Thus, the table 1 revealed as soon as a slight modification on
2
7
7
-11
the skeleton is operated, the resulting structure is deeply
impacted and a new elucidation needs to be performed.
Moreover, when comparisons with calculations exist, the
choice of the method and of the basis set appears rarely
investigated in the literature and never clear-cut
demonstrated. Considering the above subjects with our
studies on green organic synthesis and the reactivity of α-
biologically active compounds , especially imines bearing
electron-withdrawing N-substituents which are useful
intermediates and building blocks in the construction of
1
2, 13
bactericidal, fungicidal and anti-inflammatory agents.
Schiff bases are among the most versatile and useful ligands
and their metal complexes have been widely used as catalysts
1
4-17
for many organic reactions.
Some salicylmethanimine-like
2
8,
29
aminoacid phenylhydrazides
derived from (L)-α-
compounds present interesting mechanical-, thermo- or
photo- chromic behaviours for their capacity to undergo
tautomerism prototropic and many reports on the equilibrium
aminoacids herein, is reported a simple and rapid method for
the preparation of chiral Schiff bases from the coupling of
phenylhydrazides with 2-hydroxynaphthaldehyde under
solvent-free conditions. The fine characterization of these new
compounds is realized to investigate the influence of both the
aminoacid and the hydrazide function on the structure at solid
and liquid states. These data are firmly compared to quantum
chemical calculations and highlight a new and most granular
description of these structures.
1
8-20
have recently been described in the literature.
noting that Schiff bases can appear under numerous forms
Figure 1). For some examples the structure and properties
It is worth
(
have been investigated in relationship to the forms (or the mix
of the forms); the results were strongly dependent on the
electronic environment by the substituents on the aromatic
2
1
group or on the nitrogenated pendant arm, the addition of
H
R
H
R
H
R
R
H
O
N
O
N
O
NHR
H
O
H
O
N
O
N
H
H
NHR
E c
H
H
Stereochemistry a anti-E b
syn-E b
Z c
E
Z
Form
enol-imine (I)
keto-amine (II)
enolate-iminium (III)
Electronic charge
no formal
zwitterionic
d
a
Fig. 1. Representation of monomeric forms . Representations of localized π-aromatic
b
electrons are possible doubling each I and III drawn forms; the Z configuration of enol-
c
imine forms is not reported in literature; syn and anti conformations could be also
defined for the keto-amine forms according to the spatial position of N-H and N-R in
This journal is © The Royal Society of Chemistry 2018
New J. Chem., 2018, 42.| 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 11
View Article Online
DOI: 10.1039/C7NJ04597B
Paper
NJC
d
regard the oxygen atom; lot of reported studies do not distinguish the forms II and III
(mesomeric forms).
Table 1. Selected examples of Schiff bases in the literature (for a more complete comparison see SI).
1
R
2
R
3
R
Entry
Physical state
Form
Ref
1
2
3
3
4
5
6
7
8
9
H
H
H
H
Me
H
Me, alkyl
Ph or Bn
Ph
4-OMe
4-OMe
3,5-di-t-Bu
H
solid
solid
i-Pent
i-Pent
solid
II-Z
I
27
27
25
25
19
19
19
20
20
20
I (from 77 to 297 K)
I (rt) II (<140K)
Ph
CH
CH
CH
CH
CH
CH
2
CH
CH
CH
2
2
2
OH
OH
H
H
II
I minor / II major
I very major
I-E / II-Z
I / II
2
MeOH or EtOH
Tol or DMF
solid
H
H
H
H
2
OH
H
-
3
+
+
+
2
CH
CH
CH
2
SO
SO
SO
K
K
K
3-OMe
3-OMe
3-OMe
-
3
2
2
MeOH
DMSO
-
3
2
2
I
2
. Results and discussion
2
.1 Synthesis.
2
9, 30
The starting α-amino acid phenylhydrazides
3
were
obtained under mild conditions from the commercially
Scheme 2. Coupling of the 2-hydroxy-1-naphthaldehyde
phenylhydrazide 3a.
4 with (L)-alanine
available (L)-α-amino acid ester hydrochlorides 1a-e and the
phenylhydrazine
2 at 60 °C during 16 h in good yields (Scheme
1
). The condensation of (L)-alanine phenylhydrazide with the Table 2. Optimization of the reaction conditions for the coupling of the 2-hydroxy-1-
model naphthaldehyde 4 and (L)-alanine phenylhydrazide 3a.
2-hydroxy-1-naphthaldehyde
4 was studied as a
reaction to provide compound 5a (Scheme 2). The reaction
was first examined under catalytic conditions with different
solvents (Table 2).
Entry
Catalyst
SO (1)
Temperature
Time
10
Solvent
Toluene
MeOH
MeOH
MeOH
-
Yields
a
1
2
3
4
5
H
2
4
100
65
NR
PTSA (1)
14
20
b
First, we thought to study the effect of temperature because
the reactants, especially the 2-hydroxy-1-naphthaldehyde,
have a poor solubility at room temperature in the majority of
solvents (toluene, EtOH…). Nevertheless, employing of high
reaction temperature (100 °C) with 1 mol% of sulfuric acid as
catalyst during 10 h, no formation of the desired product was
observed (entry 1). The reaction performed with 1 mol% of
paratoluenesulfonic acid as catalyst in methanol during 14 h at
-
-
-
50
4
70
c
rt
20 min
5 min
71
d
100
71
a
b
No reaction was occurred.
Conditions: (L)-alanine phenylhydrazide (10 mmol), 2-hydroxynaphthaldehyde
(
c
10 mmol), under argon.
Ultrasound irradiation.
d
Microwave irradiation (startSYNTH).
It was noted that no racemization of the asymmetric carbon
atom of phenylhydrazide was occurring, based on published
65 °C allowed obtaining the compound 5a with a low yield
2
8, 29
(entry 2) due to the formation of degradation products. This is
reports
that showed no epimerization was observed when
explained by the formation of salts that causes the weakening
of yields. A further decrease of the reaction temperature to 50
mild conditions were used. We observed that products 5a-e
can not be purified by chromatography but they are stable in
air for several months at room temperature.
°
C and the reaction time to 4 h without catalyst gave the
desired coupling product and allowed to increase the yield to
0% (entry 3).
7
No conventional heating was explored performing the reaction
under ultrasound activation in methanol at room temperature
(Scheme 3 and Table 2, entry 4). The product 5a was obtained
with good yield after 20 min while the reaction performed
under microwave activation was completed in only 5 min
Scheme 3. Synthesis of Schiff bases 5a-e.
(entry 5). The Table 3 presents the synthesized Schiff bases 5a-
Table 3. Coupling of the 2-hydroxy-1-naphthaldehyde 4 and phenylhydrazides 3a-e.
e
yielded from 57 to 75 %.
a
b
c
Entry
Product
Yields Δ
Yields MW
Yields )))
1
2
3
4
5
5a (Me)
5b (i-Pr)
5c (i-Bu)
5d (Bn)
70
67
70
56
73
71
69
74
60
75
71
68
72
57
72
2
5e (HOCH )
a
Conditions: α-aminoacid phenylhydrazide (10 mmol), 2-hydroxynaphthaldehyde
10 mmol), MeOH, 4 h under argon.
(
b
Conditions of activation: microwave irradiation (startSYNTH), 100 °C, 5 min.
Conditions of activation: ultrasound irradiation, rt, 20 min.
c
Scheme 1. Synthesis of the α-amino acid phenylhydrazides 3a-e.
2
| New J. Chem., 2018, 42
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 3 of 11
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04597B
NJC
Paper
of oxygen, nitrogen, and acidic H atoms bring numerous
intramolecular electrostatic interactions. Thus, the O(23)-C(9)-
C(11)-N(12), and C(11)-N(12)-C(14)-N(15) and O(27)-C(14)-
N(15)-N(16) dihedral angles of respectively -3.5(1)°, +0.2(3)°
and -7.9(2)° indicated that the geometry is very close to the
planarity on a large region of the molecule. In the packing of
crystal structure 5b
,
intermolecular O(23)…H(15)-N(15)
hydrogen bonding contact of 1.85(2) Å is formed due to the
presence of the hydrazide function sustaining the
supramolecular framework (figure 2b). Interestingly, structures
show one medium weak (O(27)…H(12)-N(12) with 2.53(2) Å)
and two strengths (N(12)-H(12)…O(23) with 1.83(2) Å &
O(23)…H(15)-N(15) with 1.85(2) Å) hydrogen bonds. This last
intermolecular hydrogen bond is so strength that the C(9)-
O(23) bond is slightly distorted with an O(23)-C(9)-C(10)-C(1)
dihedral angle bond of 175.0(1)°. Moreover, the
supramolecular structure is reinforced by the H-π interaction
between the phenyl and naphthyl groups with a 3.010 Å value
from H to centroid. In order to elucidate the fineness of the
structure between the forms II and III, the bonds C(9)-O(23)
and C(11)-N(12) were measured with values of 1.279(2) Å and
1.307(2) Å respectively. The value of CN bonding length is in
full agreement with a III shaped writing, whereas the CO bond
3
2
denotes a character between simple and double bond.
Therefore, three intra and intermolecular hydrogen bonds
determine the structure around the nitrogen N(12) as a ( )-III
liked form, but around the oxygen O(23) an intermediate view
between ( )-III and the anti-( )-II ketoamine forms is a more
accurate of writing.
E
E
Z
2
.3 Solution NMR study.
The compounds 5a-e were found to have very poor solubility
in common organic solvents including dichloromethane,
chloroform, toluene, ethyl acetate and tetrahydrofuran but
Fig. 2. X-ray analyses (anisotropic displacement ellipsoids pictured are set at 30% they were soluble in polar solvents such as methanol,
probability): a) ORTEP of 5b (up); b) supramolecular structure (down).
acetonitrile, N,N-dimethylformamide and dimethylsulfoxide.
In general, Schiff bases in solution can exhibit several possible
3
tautomeric forms: as C-O-H…NCH in enol imino (I) and
3
2
.2 Solid state study.
3
4
C=O…H-NCH in keto-amino (II) tautomers.
1
In solution H NMR, the characterization supported by the
H(12) proton is rarely a relevant argue, since chemical shifts
Single crystal X-ray diffraction measurements for 5b were
carried out at T = 200 K with a Bruker D8 VENTURE
diffractometer equipped with
bidimensional detector using a high brilliance IµS microfocus
X-ray Mo K monochromatized radiation ( = 0.71073 Å). An
empirical absorption correction was applied using the SADABS
a
PHOTON 100 CMOS
2
6, 35
show a high solvent dependency.
protons are also sensitive to the deuterium exchange. Hence,
H(12) and hydrazide protons are unobserved in MeOD- even
. The chemical shift of the
H(11) iminomethine proton does not give no more information
Moreover, the hydrazide
α
λ
d
4
3
5-37
3
1a
31b
sometimes for both in CDCl
3
program
was solved by direct methods and refined by full-matrix least
based on the method of Blessing. The structure
3
8
13
3
1c,d
in itself as well. Nevertheless, C NMR spectroscopy in
solution clearly makes it possible to qualify the nature of the
C(9) atom as phenolic or “quinodic” carbon (often presented
squares using the SHELX-TL package.
The hydrogen atoms
were placed from the electron density in calculated positions
and were included in the refinement without restraint on the
3
9
3
1e
as such regardless of forms II or III which it belongs). For the
compounds 5a 5b 5d and 5e recorded in MeOD- , signals
were observed at 178.1, 177.6, 177.1, and 175.5 ppm
respectively, and then at 166.5 ppm for 5c recorded in CDCl
nitrogen atoms. Crystal data
of 5b are given in supporting
,
,
d
4
information, while ORTEP is presented in Figure 2 and the
selected geometrical parameters are listed in the table 5.
3
1f
3
.
Molecular graphics were generated by Mercury 3.9.
In contrast to the several Schiff bases of literature, 5b
crystallized in a unique space group . No desmotropic
These values show the quinodic nature of the carbon C(9) in
methanol at room temperature and place the position of the
H(12) atom on the nitrogen N(12), although a small amount of
1 1 1
P2 2 2
forms were observed. In the crystal structure, the succession
This journal is © The Royal Society of Chemistry 2018
New J. Chem., 2018, 42| 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 11
View Article Online
DOI: 10.1039/C7NJ04597B
Paper
NJC
1
the phenolic form can be sometimes observed in the H NMR respectively, which are attributed to the vibration of C=O
spectrum (less than 10%). In the chloroform, only one signal bands and besides, sharp bands appeared in respectively 1544,
-1
was found above 170 ppm for 5c with a value of 171.5 ppm 1543, 1546, 1545 and 1542 cm corresponding to the
ascribed to the C(14) hydrazide carbon usually at 173-174 ppm stretching vibrations of (C=N) bands. It refines at the solid
2
8, 29
in CDCl
3
or MeOD-d
4
in full agreement with the literature state the presence of the keto-amine form II or its mesomeric
4
data. Thus, the signal at 166.5 ppm reveals the phenolic form III.
0
behaviour of the carbon in complete concordance with the Interestingly, the C=O of the hydrazide function absorb at
1
3
usual observed value in this solvent. Interestingly, the
9
-1
43
1667, 1654, 1677(d), 1675, 1693 cm for 5a-e that would be
H
NMR spectrum in CDCl depicts a signal above 14 ppm, difficult to attribute and confusing because of the C=O
3
3
although the value does not prove in itself the presence of quinodic form . The IR spectra of 5a-e show broad bands
8
42b
-1
the phenolic proton for 5c. The iminomethine carbon (C11) centred at around 2981, 2788, 2950, 2746 and 2680 cm , due
+
was observed at 159.7, 160.5, 160.1, 161.2 in MeOD-d
5d 5e respectively, and then 162.2 ppm in CDCl
These values illustrate the imino character (protonated or 5a-e in the present investigation exhibit a broadband at 3334,
4
for 5a
,
to ν(HN ) modes as a result of intramolecular hydrogen bonds
N _H…O which are usually very strong. All of the Schiff bases
+
5b
,
,
3
for 5c
.
3
9
-
1
not) around the nitrogen N12.
3332, 3184, 3341 and 3313 cm assigned to
νN-H vibrations;
4
1b,
NMR experiments were pursued in DMSO-d
6
with 5b
,
5c and but once more, these ones can be easily confused with
4
ν
To have a fruitfully understanding, the out-of-plane
O-H
.
2a
5e
then three labile protons were observed with an interaction
γ
COSY) between the two NH of hydrazide function allowing to band needs to be checked. 5b absorbs with thin bandwidths at
C-O
(
-1
ascertain the attribution at about 3.37 ppm to the H(12) in 843 and 872 cm where the two enol-imine and keto-amine
3
association with the residual water. The C NMR spectrum coexist, although apparently contradictory to the
1
2
6
indicated that C(9) and C(11) resonate at approximately 175 crystallographic data. However, it is known that a slight
and 159 ppm respectively indicating a full quinodic character mechanical treatment transforms the keto-amine to the enol-
3
9
as well as the presence of a well-marked iminium function.
imine forms evidencing a solid state reactivity.
This result in DMSO solution joins the conclusions of the solid
state with a III liked form around the nitrogen N(12) and a II
ketoamine form around the oxygen O(23). A series of NOESY
2
.5 Electronic absorption spectroscopy.
experiments was performed in order to gain insight into the The optical properties of compounds 5a-e were investigated
-6
geometry. The correlation between H(2) and the H(11) protons using UV/vis absorption studies in a dilute (10 M) acetonitrile
show a Z stereochemistry relationship of the C=N bond, with a solution in the range 308–600 nm, displayed in figure 4. UV
respect of a II-shaped writing, regardless for DMSO-d
MeOD-d
6
or spectra exhibit from three up to four bands in the visible
wavelengths: about 423, 403, 363 and 350 nm (Table 4). The
4
.
At this stage, room temperature NMR experiments allow absorption band at 403 nm, arises from intermolecular π-π*
certify the exclusive (or very major) formation in methanol of transitions. The highest max value with intense absorption
λ
the anti-(Z)-II structure around the oxygen and (E)-III iminium gives access to a roughly HOMO-LUMO electronic transition,
around the nitrogen. It is quite surprising since usually the evaluated by the extrapolation of the tangent to the first
phenolic form is the exclusive one in agreement with the inflexion point. The table 4 presents herewith the optical gap
polarity of this solvent. The presence of the hydrazide energies evaluated around of Eog = 2.77 eV, corresponding to a
function, bringing a second intramolecular bond, is likely semiconductor behaviour for these Schiff bases.
responsible for this astonished result. In chloroform, the I
5
5
5
5 d
5
a
b
c
enol-imine can be sighted almost as the sole form; in
dimethylsulfoxide the results are very close to the
crystallographic data: (E)-III iminium and anti-(Z)-II quinodic
forms the environment of N(12) and O(23) respectively.
8
6
4
2
0
e
2.4 Infrared Spectroscopy.
Neat solid FT-IR spectra of the compounds 5a-e were recorded
-
1
4 0 0
5 0 0
W a ve le n g th (n m )
6 00
in the 3500–600 cm region and some characteristic stretching
vibration modes can be identified in this area. In contrast with
-6
Fig. 3. The UV-Vis spectra of the Schiff bases 5a-e in MeCN solution (10 M) at rt.
1
3
C NMR, CO function is usually not an essential parameter to
identify the I, II or III forms since C=O and C=N bands give
a
Table 4. Optical properties of the chiral compounds 5a-e.
Entry Compound
λ
max
λ
gap
E
og
4
1, 42
similar contribution to the concomitant wavelength,
especially if the both enol-imine(I) and keto-amine(II) are
1
2
3
4
5
5a
5b
5c
5d
5e
423.31, 400.49, 364.74, 341.19 447.65 2.77
423.31, 403.25; 363.13, 350.25 449.27 2.76
423.31, 403.54, 363.21, 350.28 447.65 2.77
424.04, 403.54, 363.21, 348.81 450.90 2.75
423.31, 401.22, 364.00, 350.28 447.65 2.77
19
present . However, in our cases the hydrazide function deeply
impacts the H(12) proton, as stated by the X-ray results, to get
unusual data. Indeed, the IR spectra of 5a-e depicted strong
a
-1
λ values are given in nm; energies are given in eV.
bands observed at 1625, 1616, 1625, 1617 and 1693 cm
4
| New J. Chem., 2018, 42
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 5 of 11
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04597B
NJC
Paper
5
2
2.6 Calculations.
Dunning/Huzinaga gave poor results. Basis including diffuse
functions gave unsatisfactory results (entries 27 and 28).
Method calculations and basis sets
The restraint free geometry optimization of species was Diffuse functions are used for atoms with high number of
performed using the Gaussian 09 software
with standard electrons and anions but give bad results for cations. Indeed,
parameters and
tight criteria of convergence. The the part charged negatively should be roughly dispersed in the
4
4
a
determination of structures in solution was carried out using aromatic cycle, whereas the part charged positively would be
the self-consistent reaction field (SCRF) method. Transition very localized on the nitrogen due to the iminium form; the
states were located without constraint along their cationic character prevails over the anionic one.
corresponding reaction pathways, characterized by a sole To summarize, the employment of a very high angular moment
imaginary frequency, checking out the connection with the basis is not needed to reach an accurate geometry and brings
ground and final states. Final predicted energies included the only very few enhancements in results towards of moderately
zero-point vibrational and thermal energy corrections at polarized functions. Thus, the use of heavy basis sets appears
2
98.15 K (see SI), giving the Gibbs free energy in the both gas interesting only with the aim at studying chemical pathways or
phase and solvent solution for minima and maxima of the getting properties. Finally, an optimization at a BMK/6-
potential electrostatic surface. The molecule 5b was chosen as 31G(2df,2pd) is the best compromise in terms of
a model and the Cartesian coordinates obtained by X-ray data computational time and high level of accuracy to successfully
were used as starting point for the geometrical optimization.
investigate the potential energy surface with the geometrical
Several geometrical parameters (distances, angles and minima, the transition state and the physical properties.
dihedral angles, see figure 2a) of the species 5b including
Static approach
The geometry is quite similar between the cristallographic data
crucial nitrogen and oxygen atoms, especially charged atoms
were selected to appreciate the relevance of the calculated
and the gas phase (Figure 4). A notable difference is the more
geometries. The relative difference between calculated and
important planarity in the gas phase concerning the naphthyl
experimental values was evaluated over the whole
cycle and its close heavy adjacent atoms. In fact, in the sole
parameters; Hartree-Fock (HF) and DFT methods were tested
molecule the dihedral angles O(23)-C(9)-C(10)-C(11) and C(9)-
in the gas phase and results summarized in the Table S4 (see
C(10)-C(11)-N(12) are -3° and +3° respectively (vs -9.9(2)° and
ESI).
4
5
+5.8(2)° for the solid state). This gap with the gas phase can
likely be attributed to the supramolecular electrostatic stack,
which contributes to twist the more ionic region (Figure 2b). A
singular point is the presence of a second intramolecular
hydrogen bond inherent to the hydrazide function.
Consequently, two labile hydrogens are approximately aligned
with one oxygen atom with an H(12)-C(14)-O(27)-H(16)
dihedral angle of 169.0(7)° leading to an increased
rigidification of the conformation. The position of the amino
acid residue is placed to minimize the electrostatic repulsion
with the hydrazide function and the enolate-iminium part
First attempts HF and DFT-B3LYP methods were tested for
the screening of the basis sets (entries 1-10). Surprisingly 3-
21G gave good results with both HF and B3LYP methods to
approach the more accurate values of the geometrical
parameters (entries 1 and 6). However to take into account
the electronic dispersion for further calculations (pathways
and properties), a more extended basis set was required. Thus,
diffuse (+) and polarized (d and/or p) functions were added on
hydrogen or heavy atoms. Several DFT methods were tested
4
6
(
entries 10-21). By example, the M062X DFT method (entry
5) underestimates the hydrogen bonds in favour of a
combination of the approaches of the two aromatic goups
without -stacking interactions being strongly stated, the
1
(Figure 5). Thus, the isopropyl group is considered such as the
bulky group where the both methyls do not superpose to the
nitrogen- and oxygen-containing region that is to say the
hydrogen (H24) is oriented above it and the two methyl groups
at the opposite. Curiously, the spatial arrangement of the
phenyl group is close to those of the solid state revealing that
π
resulting structure is so clearly different of the X-ray data.
Unexpectedly, DFT methods including dispersion terms and
4
long range correction CAM-B3LYP were not better than the
7
4
8
classic ones (entries 19 and 21). Although PBE1PBE,
ω
B97XD
and B3P86 methods (entries 11, 16 and 21), often used in
the literature, gave correct results but were not the best
4
9
50
the intermolecular H-π interaction in the solid state (vide
supra) is not essential to maintain its conformation.
5
1
The examination of the charge distribution is fruitful in the gas
phase (table 5). The anionic character of O(23) is clearly
evidenced whatever the model is, with the adjacent carbon
C(9) which offsets this charge showing a phenolic behaviour of
the CO bond (entries 1 and 2). The nitrogen N(12) bears also a
partial negative charge and the hydrogen H(12) can be
therefore considered as its counter ion (entries 5 and 6).
methods to describe the geometry. BMK was clearly found
as the full adequate DFT method to reach the geometry of the
structure (entry 14).
Fixing the BMK DFT method, basis sets were established
(entries 22-32). Once more 3-21G was found as the basis set
the closer of the X-ray data to get the most accurate value of
bond length; angle values are acceptable as well, but dihedral
angle values were enough different from the crystallographic
data leading to a high value of the MAD (entry 22). Triple-split
valence zeta basis are not better sets than double-split valence
ones (compare entries 23 with 25, 24 with 26). Full (D95, entry
Atoms C(10) and C(11) are less affected, but have
a
distribution of charges in agreement with the expected writing
for mesomeric forms (entries 3 and 4). To sum up, although
the geometries are very close, the ionic character in the gas
phase is more expressed than in solid one.
29) or valence (D95V, entry 30) double-zeta basis of
This journal is © The Royal Society of Chemistry 2018
New J. Chem., 2018, 42| 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 11
View Article Online
DOI: 10.1039/C7NJ04597B
Paper
NJC
Figure 4. Optimized geometries at a BMK/6-31G(2df,2pd) level in the gas phase for 5b:
Table 6. Minimum inhibitory concentration (MIC) and minimum bacterial concentration
(MBC) in mg/mL of the compounds 5a-e against selected bacteria.
enol-imine form (left) and TS from one form to another (right).
Entry
Cmpd
E. coli
S. aureus
Ca
S.E
P.S
B.S
MIC
MBC
0.18
MIC
MBC
0.18
0.37
1.5
MIC
MBC
0.37
0.37
1.5
MIC
MBC
0.37
0.37
1.5
MIC
MBC
0.37
0.37
1.5
MIC
MBC
0.37
0.37
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
1
2
3
4
5
5a
5b
5c
5d
5e
0
.37
1.5
.5
1.5
.5
1.5
.5
1.5
.5
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
1.5
1.5
1.5
1.5
1.5
1.5
0.75
1.5
1.5
Dynamic approach
1
1.5
1.5
1.5
Using the BMK/6-31G(2df,2pd) method and basis set in the gas
1.5
1.5
0.75
1.5
1.5
-1
phase, the 5b enol-imino form was found 2.4 kJ.mol less
1
1.5
1.5
1.5
stable than the keto-amino one (Figure 4). The transition state E. coli: Escherichia coli, S. aureus: Staphylococcus aureus, Ca: Candida
albicans, S.E: Salmonella enterdis, P.S: Pseudomonas aeruginosa, B.S
:
(
TS) from the keto-amine to the enol-imine was located with a Bacillus subtilis
-1
#
barrier energy of
ꢀG = 9.7 kJ.mol . The hydrogen bonding
N(12)…H…O(23) in the TS rises to the equal distance values
between nitrogen and oxygen atoms (1.218 and 1.249 Å) then
changes in the enol form (N…H-O) with 1.698 and 0.989 Å.
Besides, the hydrazide second intramolecular hydrogen
bonding is moving from the keto-amino form 2.818, to 2.289 in
TS and up to 2.273 Å for the enol-imine showing the deep
involvement in the H transfer but without affecting the
coexistence of this second hydrogen bond.
2
.7 Biological activity.
First, analgesic activity of all the Schiff bases was tested in vivo
using the carrageenan-induced rat paw oedema test.
Unfortunately, no analgesic activity was observed. The
synthesized
Schiff
bases
were
screened
against
microorganisms such as E. coli, S. aureus, B. subtilis, Candida
albicans, Salmonella enterdis and Pseudomonas aeruginosa to
assess their potential as antimicrobial agent. The antibacterial
activity was evaluated using the Disc Diffusion method. The
stock solution of the test compound was prepared by
dissolving 3 mg of the test compound in 1 mL of DMSO
solvent. The bacteria were subcultured in agar medium. The
petri dishes were incubated for 24 h at 37 °C. Gentamycine
was also screened under similar conditions as the reference
drug. The zones of inhibition based upon zone size around the
discs were taken approximately. The minimum inhibitory
a
Table 5. Selected values for the charge distribution of 5b in the gas phase.
Atomic charge model
Entry Atom
ESP-derived
b
b
Mulliken
Natural
c
c
CHelpG scheme
MK scheme
1
2
3
4
5
6
O(23)
C(9)
-0.43
0.31
-0.17
0.04
-0.31
0.32
-0.59
0.44
-0.23
0.13
-0.54
0.46
-0.60
0.66
-0.31
0.14
-0.32
0.35
-0.53
0.57
-0.39
0.07
C(10)
C(11)
N(12)
H(12)
-0.09 concentration was determined using the microdilution
0.31 method. It was defined as the lowest concentration of the
a
Calculated at a MP2/6-31G(2df,2pd) on the BMK/6-31G(2df,2pd) optimized tested product that completely suppresses cell growth.
geometry, see ESI for more details.
However, a Minimal Bactericidal Concentration (MBC) was
defined as the lowest concentration of the extract that kills
b
53
54
Mulliken or natural population analyses.
c
55
Electrostatic potential (ESP)-derived charges using the CHelpG or Merz-
5
7
5
6
99.99% of the tested bacteria.
The MIC and MBC values of these compounds against the
Kollman-Singh schemes.
Figure 5. Synoptic of the thin description of the Schiff bases according to the physical growth of microorganisms are summarized in table 6. All the
state.
structures presented a good antibacterial activity against six
bacterial strains. This is attributed to hydrogen bonding
between the cellular constituents of the bacterial cell. A small
group (Me) for the aminoacid gives a best hit (entry 1),
whereas moiety offering a supplementary hydrogen bond on
the pendant arm does not involve no enhancement (entry 5).
It is also concluded that imine and hydroxyls groups play a key
role in improving the antibacterial activity.
Bulky
Bulky
H
N
R
R
~
Planar region
H
N
N
NH
H
HN
*
H
O
O
+
H
N
δ−
O
OH
3. Conclusions
δ−
An efficient method for the synthesis of enantiopure imines
Gas and solid states
00% in DMSO or 90% in MeOH
via
the
condensation
of
α-aminoacid-derivated
1
90% in CHCl3
6
| New J. Chem., 2018, 42
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 7 of 11
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04597B
NJC
Paper
phenylhydrazides with the 2-hydroxynaphthaldehyde, has (578 nm). UV-Visible spectra were recorded on a Jasco V-530
been established. These compounds have been characterized UV-Visible spectrometer in the range 200-800 nm. Microwave
1
13
by H, C-NMR, IR, HRMS, UV–visible spectroscopies and irradiations were realized using a programmed microwave
structural X-ray diffraction methods. The first overview of this synthesis reactor (START SYNTH, Microwave synthesis
work is the astonishing non correlation between the Labstation). All biological experiments were performed
environment around the oxygen and the nitrogen atoms of according to the Guide lines for Animal Experimentation of
these Schiff bases. Thus, the structure completely behaves Monastir University.
neither as an enolate-iminium (III) nor as a keto-amine (II)
(figure 5). Secondly, the hydrazide function provides a second 4.2. General procedures
intramolecular bonding which deeply impacts the structure.
The rigidification is so important that the phenolic form is not
obtained in the methanol.
Conventional heating
A mixture of 2-hydroxynaphthaldehyde (1.7 g, 10 mmol, 1 eq)
and α-aminoacid phenylhydrazide (10 mmol, 1 eq) in methanol
At the solid state, hydrazide function and two intramolecular
hydrogen bonds involve a shape close to the planarity for the
whole nitrogen- and oxygen- containing region. The freshly
prepared Schiff bases have a (E)-III form around the nitrogen
(
5 mL) was heated under argon at 50 °C for 4 h. The yellow
colored precipitate was cooled at room temperature, filtered,
washed by cooled methanol and dried in air.
Microwave irradiation
(
i.e. iminium) and an intermediate form between (E)-III and
Z)-II for the oxygen (figure 5). These very air-stable Schiff
2
-hydroxynaphthaldehyde (1.7 g, 10 mmol, 1 eq) was mixed
(
with α-aminoacid phenylhydrazide (10 mmol, 1 eq) in closed
vessel and the mixture was irradiated in microwave oven for 5
min at 350 watt. The yellow colored precipitate was filtered,
washed by cooled methanol and dried in air. This synthesis
bases are able to reveal a solid state reactivity under a slight
mechanical treatment converting in part the initial II/III form
to the enol-imino I form. The BMK/6-31G(2df,2pd) method
and basis sets in the gas phase are adapted to describe the
geometry; diffuse functions and dispersion terms damage the
geometrical description. The in-vitro antibacterial study
indicated that the structures 5a-e exhibited good activities
against Escherichia coli, Staphylococcus aureus, Candida
albicans, Salmonella enterdis, Pseudomonas and Bacillus
subtilis.
processes was performed on
synthesis reactor (START SYNTH).
Ultrasound activation
a programmed microwave
A mixture of 2-hydroxynaphthaldehyde (1.7 g, 10 mmol, 1 eq)
and α-aminoacid phenylhydrazide (10 mmol, 1 eq) in methanol
(
5 mL) was suggested to ultrasound activation. The yellow
colored precipitate was filtered, washed by cooled methanol
and dried in air.
4
. Experimental
4
.3. Compound characterization
E)-1-(((1-oxo-1-(2-phenylhydrazinyl)propan-2-
yl)iminio)methyl)naphthalen-2-olate (5a): Yield 68%. Yellow
All reactions were carried out under an argon atmosphere in solid; mp 173-175 °C; R 0.16 (EtOAc/c-C H = 40/60); [α] = -
(
4.1. General comments
f
6
12
578
-
1
round-bottomed flasks equipped with magnetic stirrer. All 26 ± 3 (MeCN, C= 0.078 ± 0.004). FT-IR (neat), νmax (cm ):
solvents were freshly distilled before use. Melting points were 3334, 3230, 2981, 1625, 1598; H-NMR (300 MHz, MeOD-d ):
1
4
determined on a Buchi 510 capillary apparatus. NMR spectra δ= 1.69 (d, 3H, J= 6.9 Hz, H24), 4.54 (q, 1H, J= 6.9 Hz, H13),
were recorded on a Bruker AC 300 spectrometer [300 MHz 4.62 (brs, 3H, NH15, NH16, H12), 6.73-6.88 (m, 4H, H8, H18,
1
(
13
H) and 75 MHz ( C)]. NMR spectra were calibrated on the H20, H22), 7.16 (t, 2H, J= 7.9 Hz, H19 and H21), 7.26 (t, 1H, J=
non-fully deuteried residual solvent signal (ppm): in DMSO-d
7.6 Hz, H4), 7.47 (t, 1H, J= 7.3 Hz, H3), 7.64 (d, 1H, J= 7.5 Hz,
at 2.50 (proton) and 39.52 (carbon), in CDCl at 7.26 (proton) H5), 7.78 (d, 1H, J= 9.3 Hz, H7), 8.06 (d, 1H, J= 8.4 Hz, H2), 9.14
and 77.16 (carbon), in MeOD-d at 3.31 (proton) and 49.00 (s, 1H, H11); C-NMR (75 MHz, MeOD-d ): δ= 20.40 (C24),
carbon). Proton and carbon attribution numbers refer to X-ray 60.53 (C13), 108.29 (C10), 114.10 (C18 and C22), 119.67 (C2),
6
3
1
3
4
4
(
data (figure 2a) and /or the spectrum section (see ESI). Fourier 121.26 (C20), 124.19 (C4), 125.18 (C8), 127.77 (C6), 129.48
transformed-IR spectra were recorded on a Nicolet 6700 ATR, (C3), 130.02 (C19 and C21), 130.23 (C5), 135.47 (C1), 139.57
-1
to support with Diamond accuracy ± 1 cm . Electrospray (C7), 149.71 (C17), 159.72 (C11), 173.15 (C14), 178.13 (C9)
ionisation (ESI) mass spectroscopy data of compounds 5a-e ppm; ESI(+)-MS CH CN [C= 0.5, SC= 30, EC= 3] m/z (rel. int.):
3
+
+
+
were recorded on an UPLC Waters device (in positive mode); 334 (100, M+H ), HRMS ES for C H N O m/z: [M+H] Calc.
2
0 20 3 2
for the voltages of the mass spectroscopies, the following 334.1556, found: 334.1553.
abbreviations are used: C Capillary (kV), SC Sampling Cone, EC (E)-1-(((3-methyl-1-oxo-1-(2-phenylhydrazinyl)butan-2-
Extraction Cone. Calibration was performed with sodium yl)iminio)methyl)naphthalen-2-olate (5b): Yield 67%. Yellow
-
1
formate (range from 100 to 1000 g.mol ) and the lockspray solid; mp 179-181 °C; R 0.33 (EtOAc/c-C H = 40/60); [α] = -
f
6
12
578
-1
-1
(
lockmass on the leucine encephaline 556.2771 g.mol ) was 53 ± 3 (MeCN, C= 0.098 ± 0.004). FT-IR (neat), ν
used without collision energy; the relative intensity of peaks is 3332, 2969, 2788, 1616, 1595; H-NMR (300 MHz, MeOD-d ):
max
(cm ):
1
4
given in brackets. Optical rotations were measured by using a δ= 1.09 (d, 3H, J= 7.8 Hz, Me), 1.11 (d, 3H, J= 7.8 Hz, Me), 2.39-
Perkin Elmer Polarimeter (Model 341) using a mercury lamp 2.48 (m, 1H, H24), 4.09 (d, 1H, J= 6.9 Hz, H13), 6.78-6.89 (m,
This journal is © The Royal Society of Chemistry 2018
New J. Chem., 2018, 42| 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 11
View Article Online
DOI: 10.1039/C7NJ04597B
Paper
NJC
1
4
H, H8, H18, H20 and H22), 7.16 (t, 2H, J= 7.9 Hz, H19 and 3341, 3021, 2746, 1617, 1545; H-NMR (300 MHz, MeOD-d
H21), 7.27 (t, 2H, J= 7.7 Hz, 1H, H4), 7.46-7.51 (m, 1H, H3), 7.66 δ= 3.22 (dd, 1H, J= 13.3, 7.9 Hz, H24), 3.44 (dd, 1H, J= 13.2, 6.9
d, 1H, J= 7.5 Hz, H5), 7.80 (d, 1H, J= 9.3 Hz, H7), 8.06 (d, 1H, J= Hz, H24), 4.59 (t, 1H, J= 7.5 Hz, H13), 6.59 (d, 2H, J= 7.5 Hz, H18
4
):
(
1
8
0
1
.4 Hz, H2), 9.08 (s, 1H, H11); H-NMR (300 MHz, DMSO-d
.99 (d, 6H, J= 7.8 Hz, 2 × Me), 2.20-2.44 (m, 1H, H24), 3.38 (s, H8), 7.10 (t, 2H, J= 7.9 Hz, H19 and H21), 7.15-7.30 (m, 4H, H4,
H, H12 + H O), 4.14-4.18 (m, 1H, H13), 6.61-6.78 (m, 3H, H18, H27, H28, H29), 7.30-7.36 (m, 3H, H26, H30), 7.41 (t, 1H, J= 7.8
6
): δ= and H22), 6.77 (t, 1H, J= 7.2 Hz, H20), 6.85 (d, 1H, J= 9.3 Hz,
2
H20 and H22), 6.82 (d, 1H, J= 9.3 Hz, H8), 7.13 (t, 2H, J= 7.3 Hz, Hz, H3), 7.63 (d, 1H, J= 7.8 Hz, H5), 7.78 (t, 2H, J= 8.5 Hz, H2,
1
3
H19 and H21), 7.25 (t, 1H, J= 7.3 Hz, H4), 7.48 (t, 1H, J= 7.5 Hz, H7), 8.78 (s, 1H, H11); C-NMR (75 MHz, MeOD-d
4
): δ= 41.42
H3), 7.69 (d, 1H, J= 7.5 Hz, H5), 7.79 (d, 1H, J= 9.3 Hz, H7), 7.91 (C24), 67.64 (C13), 108.23 (C10), 114.09 (C18 and C22), 119.59
(
s, 1H, NH16), 8.14 (d, 1H, J= 8.4 Hz, H2), 9.19 (s, 1H, H11), (C2), 121.16 (C20), 124.19 (C4), 124.75 (C8), 128.28 (C6),
1
3
1
4
0.11 (s, 1H, NH15); C-NMR (75 MHz, MeOD-d ): δ= 18.31 129.32 (C3), 129.85 (C19, C21 and C28), 129.94 (C27 and C29),
(C25 or C26), 19.64 (C26 or C25), 33.05 (C24), 72.30 (C13), 130.19 (C5), 130.88 (C25), 130.95 (C26 and C30), 137.40 (C1),
1
00.00 (C10), 114.37 (C18 and C22), 119.63 (C2), 121.36 (C20), 139.29 (C7), 149.46 (C17), 160.13 (C11), 171.92 (C14), 177.02
24.25 (C4), 124.92 (C8), 127.95 (C6), 129.44 (C3), 129.97 (C19 (C9); ESI(+)-MS CH CN [C= 0.5, SC= 30, EC= 3] m/z (rel. int.):
1
3
+
and C21), 130.25 (C5), 135.45 (C1), 139.33 (C7), 149.79 (C17), 410 (100, M+H ), HRMS ES for C26
+
+
m/z: [M+H] Calc.
H
24
N
3
O
2
1
60.46 (C11), 172.22 (C14), 177.63 (C9); C-NMR (75 MHz, 410.1869, found: 410.1872.
3
1
DMSO-d
6
): δ= 17.61 (C25 or C26), 19.08 (C26 or C25), 31.28 (E)-1-(((3-hydroxy-1-oxo-1-(2-phenylhydrazinyl)propan-2-
(
C24), 69.89 (C13), 106.47 (C10), 112.17 (C18 and C22), 118.73 yl)iminio)methyl)naphthalen-2-olate (5e): Yield 73%. Yellow
C20), 118.85 (C2), 122.64 (C4), 124.44 (C8), 125.66 (C6), solid; mp 206-207°C; R 0.1 (EtOAc/c-C 12= 40/60); [α]578= -26
28.01 (C3), 128.77 (C19 and C21), 128.98 (C5), 133.91 (C1), ± 4 (MeCN, C= 0.060 ± 0.004). FT-IR (neat), νmax (cm ): 3024,
(
f
6
H
-1
1
1
1
37.00 (C7), 149.18 (C17), 159.45 (C11), 169.48 (C14), 174.99 2849, 1693, 1625; H-NMR (300 MHz, MeOD-d
4
): δ= 4.00 (dd,
= 5.1
(C9) ppm; ESI(+)-MS CH
+
3
CN [C= 0.5, SC= 30, EC= 3] m/z (rel. 1H, J = 10.8 Hz, J = 6.9 Hz), 4.10 (dd, 1H, J = 10.8 Hz, J
1
1
2
2
+
+
int.): 362 (100, M+H ), HRMS ES for C22
Calc. 362.1860, found: 362.1873.
H
24
N
3
O
2
m/z: [M+H]
Hz), 4.45-4.49 (m, 1H), 6.81-6.89 (m, 5H), 7.15-7.27 (m, 4H),
7.45-7.50 (m, 1H), 7.65 (d, 1H, J= 7.8 Hz), 7.78 (d, 1H, J= 9.00
1
Hz), 8.06 (d, 1H, J= 8.4 Hz), 9.14 (s, 1H); H-NMR (300 MHz,
(E)-1-(((4-methyl-1-oxo-1-(2-phenylhydrazinyl)pentan-2-
yl)iminio)methyl)naphthalen-2-olate (5c): Yield 70%. Yellow DMSO-d
solid; mp 181-183 °C; R 0.39 (EtOAc/c-C 12= 40/60); [α]578= - 4.46 (dd, 1H, J= 11.2, J= 5.8 Hz, H13), 5.33-5.47 (m, 1H, OH),
8 ± 6 (MeCN, C= 0.060 ± 0.004). FT-IR (neat), νmax (cm ): 6.65-6.85 (m, 4H, H8, H18, H20 and H22), 7.13 (t, 2H, J= 7.8 Hz,
6
): δ= 3.71-3.86 (m, 1H, H24), 3.86-4.00 (m, 1H, H24),
f
6
H
-1
6
3
0
1
184, 3024, 2950, 1625, 1546; H-NMR (300 MHz, CDCl
.96 (d, 6H, J= 6.0 Hz), 1.68-1.72 (m, 1H), 1.95 (dd, 2H, J
= 5.7 Hz), 4.21-4.26 (m, 1H), 6.81 (d, 2H, J= 7.8 Hz), 6.86- (d, 1H, J= 1.8 Hz, NH16), 8.08 (d, 1H, J= 8.4 Hz, H2), 9.12 (d, 1H,
3
): δ= H19 and H21), 7.23 (t, 1H, J= 7.3 Hz, H4), 7.47 (t, 1H, J= 7.2 Hz,
1
= 7.5 H3), 7.67 (d, 1H, J= 7.5 Hz, H5), 7.77 (d, 1H, J= 9.3 Hz, H7), 7.86
Hz, J
2
1
3
6
7
1
6
1
.91 (m, 1H), 7.11-7.22 (m, 4H), 7.36 (t, 1H, J= 7.8 Hz), 7.51- J= 8.7 Hz, H11), 10.09 (d, 1H, J= 1.8 Hz, NH15); C-NMR (75
.56 (m, 1H), 7.73-7.84 (m, 2H), 8.01-8.07 (m, 2H), 9.18 (s, 1H), MHz, MeOD-d ): δ= 64.36, 68.08, 108.71, 113.99, 114.35,
): δ= 0.97 (d, 3H, J= 119.78, 121.34, 124.22, 124.79, 128.01, 129.39, 129.98,
.9 Hz, Me), 0.99 (d, 3H, J= 6.6 Hz, Me), 1.51-1.72 (m, 1H, H25), 130.20, 135.45, 139.19, 139.79, 149.63, 161.17, 171.06,
4
1
4.29 (s, 1H); H-NMR (300 MHz, DMSO-d
6
1
3
6
.72-1.94 (m, 2H, H24), 3.38 (s, 1H, H12), 4.40-4.54 (m, 1H, 176.82, C-NMR (75 MHz, DMSO-d ): δ= 62.83 (C24), 65.65
H13), 6.66-6.76 (m, 3H, H18, H20 and H22), 6.83 (d, 1H, J= 9.3 (C13), 106.43 (C10), 112.26 (C18 and C22), 118.72 (C2 and
Hz, H8), 7.12 (t, 2H, J= 8.2 Hz, H19 and H21), 7.26 (t, 1H, J= 7.2 C20), 122.53 (C4), 124.75 (C8), 125.58 (C6), 128.00 (C3), 128.75
Hz, H4), 7.49 (t, 1H, J= 7.2 Hz, H3), 7.70 (d, 1H, J= 7.8 Hz, H5), (C19 and C21), 128.98 (C5), 134.08 (C1), 137.06 (C7), 149.98
7
.80 (d, 1H, J= 9.6 Hz, H7), 7.90 (s, 1H, NH16), 8.15 (d, 1H, J= (C17), 159.33 (C11), 168.37 (C14), 175.47 (C9) ppm; ESI(+)-MS
+
3
8.4 Hz, H2), 9.26 (d, 1H, J= 6.3 Hz, H11), 10.14 (s, 1H, NH15); CH CN [C= 0.5, SC= 30, EC= 3] m/z (rel. int.): 350 (100, M+H ),
1
3
+
+
3 20 3 3
C-NMR (75 MHz, CDCl ): δ= 21.35, 23.07, 24.59, 43.01, 69.52, HRMS ES for C20H N O m/z: [M+H] Calc. 350.1505, found:
1
1
1
08.41, 113.76, 118.98, 120.80, 121.43, 123.64, 127.57, 350.1510.
28.16, 129.17, 129.30, 132.84, 136.05, 147.71, 162.16,
3
1
6
66.48, 171.51; C-NMR (75 MHz, DMSO-d ): δ= 21.95 (C26 or
Conflicts of interest
C27), 22.70 (C27 or C26), 24.42 (C25), 41.86 (C24), 62.75 (C13),
1
06.64 (C10), 112.14 (C18 and C22), 118.73 (C20), 118.93 (C2),
22.71 (C4), 124.08 (C8), 125.78 (C6), 127.99 (C3), 128.75 (C19
There are no conflicts to declare.
1
and C21), 128.98 (C5), 133.76 (C1), 136.86 (C7), 149.09 (C17),
59.22 (C11), 170.07 (C14), 174.15 (C9) ppm; ESI(+)-MS CH
1
3
CN Acknowledgements
+
C= 0.5, SC= 30, EC= 3] m/z (rel. int.): 376 (100, M+H ), HRMS
[
The authors thank the DGRSRT (Direction Générale de la
Recherche Scientifique et de la Rénovation Technologique) of
the Tunisian Ministry of Higher Education and Scientific
research and Technology for financial support of this research.
+
+
ES for
76.2028.
E)-1-(((1-oxo-3-phenyl-1-(2-phenylhydrazinyl)propan-2-
yl)iminio)methyl)naphthalen-2-olate (5d): Yield 56%. Yellow
solid; mp 197-199 °C; R 0.35 (EtOAc/c-C 12= 40/60); [α]578= -
80 ± 11 (MeCN, C= 0.068 ± 0.004). FT-IR (neat), νmax (cm ):
23 26 3 2
C H N O m/z: [M+H] Calc. 376.2025, found:
3
(
f
6
H
-
1
1
8
| New J. Chem., 2018, 42
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 9 of 11
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04597B
NJC
Paper
Crystal Structure Determination, Siemens Analytical X-ray
Instrument Division : Madison, WI USA, 1994; e) these data
Notes and references
1
2
H. Schiff, Euro. J. Org. Chem., 1864, 131, 9–118.
can
www.ccdc.cam.ac.uk/data_request/cif; C H N O , Mw
be
obtained
free
of
charge
via
=
M. Enamullah, A. B. Uddin, G. Pescitelli, R. Berardozzi, G.
Makhloufi, V. Vasylyeva, A. C. Chamayou and C. Janiak,
Dalton Trans., 2014, 43, 3313–3329.
2
2
23
3
2
361.43, orthorhombic, space group P2 2 2 ; dimensions: a =
1 1
1
10.3964(5) Å, b =10.8708(5) Å, c = 17.5190(7) Å, V =
3
-3
-1
3
4
5
6
M. Enamullah, V. Vasylyeva and C. Janiak, Inorg. Chim. Acta.,
1979.95(15) Å ; Z = 4; Dx = 1.213 Mg m ; µ = 0.08 mm ;
117330 reflections measured at 200 K; independent
2013, 408, 109–119.
S. Y. Ebrahimipour, I. Sheikhshoaie, A. Crochet, M. Khaleghi
and M. K. Fromm, J. Mol. Struct., 2014, 1072, 267–276.
reflections: 5839 [5372 Fo > 4
to a 2 max value of 60.2° (99.8 % coverage). Number of
variables: 258; R = 0.0345, wR = 0.0903, S = 1.048; highest
σ(Fo)]; data were collected up
Θ
K. C. Gupta and A. K. Sutar, Coord. Chem. Rev., 2008, 252
420–1450.
M. Rezaeivala and H. Keypour, Coord. Chem. Rev., 2014, 280
03–253.
,
1
2
–
3
1
residual electron density 0.24 e.Å ; CCDC = 1577687; f) C. F.
Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P.
McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de
Streek and P. A. Wood, J. Appl. Cryst., 2008, 41, 466–470.
32 Usual bond values (Å) for molecular solids are 1.22 (C=O),
1.43 (C-O), then 1.30 (C=N), 1.47 (C-N).
,
2
7
8
9
C. Cimarelli and G. Palmieri, Tetrahedron, 2000, 56, 475–478.
C. P. Singh and H. Hasan, Asian J. Chem., 2003, 15, 49–52.
A. Song, X. Wang and K. S. Lam., Tetrahedron Lett., 2003, 44
755–1758.
0 K. Neuvonen and K. Pihlaja, J. Chem. Soc. Perkin Trans., 1988,
61–467.
1 V. Y. Korotaev, V. Y. Sosnovskikh, I. B. Kutyashev, A. Y.
,
1
33 P. Hande, C. Albayrak, O. Mustafa, S. Ismet and B. Orhan, J.
Chem Crystallogr., 2008, 38, 901–905.
34 H. Karabıyık, I.N. Ocak, H. Petek, C. Albayrak and E. Aǧar, J.
Mol. Struct., 2008, 873, 130.
1
1
4
Barkov, E. G. Matochkina and M. I. Kodess, Tetrahedron, 35 M. Juribasic, N. Bregovic, V. Stilinovic, V. Tomisic,M.
2
008, 64, 5055–5060.
Cindric,P. Sket, J. Plavec, M. Rubcic and K. Uzarevic, Chem.
Eur. J., 2014, 20, 17333–17345.
1
1
1
2 M. S. Y. Khan, R. M. Khan and S. Drabu, Indian. J. Heterocycl.
Chem., 2001, 11, 119–122.
3 S. Cao, X. Qian, G. Song and Q. Huang, J. Fluorine Chem.,
36 G. O. Dudek and G. P. Volpp, J. Am. Chem. Soc., 1963, 85
2697–2702.
,
2
002, 117, 63–66.
37 P. Przybylski, W. Lewandowska, B. Brzezinski and F. Bartl, J.
Mol. Struct., 2006, 797, 92–98.
4 S. M. Seyedi, R. Sandaroos and G. H. Zohuri, Chin. Chem.
Lett., 2010, 21, 1303–1306.
1
38 For Schiff bases, H NMR usual chemical shifts (ppm) are the
1
1
5 L. Yin, X. Jia and X. S. Li, Chin. Chem. Lett., 2010, 21, 774–777.
6 Y. L. Yang, N. N. Wan, M. P. Wang, Z. F. Xie and J. D. Wang,
Chin. Chem. Lett., 2011, 22, 1071–1074.
following in deutered solvents at rt: a) C-OH phenolic proton
13.7–14.0 (DMSO, ref 22, 27, 35), 14.1 (DMF, ref 35) 12.7
3
(CDCl , ref 35), 13.3 (MeCN, ref 35); b) N-H…O=C 10–12
1
1
7 K. Yamaguchi, S. Koshino, F. Akagi, M. Suzuki, A. Uehara and
S. Suzuki, J. Am. Chem. Soc., 1997, 119, 5752–5753.
8 T. M. Krygowski, K. Wozniak, R. Anulewicz, D. Pawlak, W.
(DMSO, ref 22); c) HC=N…H-O imininomethine proton 8.3–
8.9 (DMSO, ref 18, 22, 27), 9.4–9.5 (DMSO or MeCN or CDCl3
or DMF, ref 35), 9.3 (MeOD, ref 35).
1
3
Kolodziejski, E. Grech and A. Szady, J. Phys. Chem., 1997, 39 For Schiff bases, C NMR usual chemical shifts (ppm) are the
1
01, 9399–9404.
following in deutered solvents at rt: a) C-OH phenolic carbon
152.8 (DMSO, ref 22), 167 (CDCl , ref 19), 160 (MeOD or
1
2
2
2
2
2
9 O. Dominguez, B. Rodriguez, M. Rodriguez, A. Ariza, N.
Farfan and R. Santillan, New J. Chem., 2011, 35, 156–164.
0 R. Pis-Diez, G. A. Echeverria, O. E. Piro, J. L. Jios and B. S.
Parajon-Costa, New J. Chem., 2016, 40, 2730–2740.
3
MeCN, ref 26); b) C=O quinodic carbon 178 (DMSO, ref 24),
172 (CDCl , ref 24); c) C-N iminomethine carbon 166 (DMSO,
3
ref 24), 164 (CDCl , ref 24).
3
1 P. M. Dominiak, E. Grech, G. Barr, S. Teat, P. Mallinson and K. 40 C. Abbas-Quinternet, PhD thesis, Synthèse et études
Wozniak, Chem. Eur. J., 2003,
9
, 963–970.
structurales de nouveaux 2:1-[α/aza]-oligomères, vers de
nouveaux foldamères, Nancy Université, Institut National
Polytechnique de Lorraine, 5 octobre 2009, p.132–157, free
access online.
2 A. C. González-Baró, R. Pis-Diez, B. S. Parajón-Costa and N. A.
Rey, J. Mol. Struct., 2012, 1007, 95–101.
3 H. Pizzala, M. Carles, W. E. E. Stone and A. Thevand, J. Chem.
Soc., Perkin Trans., 2000,
4 A. Filarowski, A. Koll, T. Glowiak, E. Majewski and T.
Dziembowska, Ber. Bunsen-Ges. Phys. Chem., 1998, 102
93–397.
5 K. Ogawa and J. Harada, J. Mol. Struct., 2003, 647, 211–216.
6 M. Rubcic, K. Uzarevic, I. Halasz, N. Bregovic, M. Malis, I.
Dilovic, Z. Kokan, R. S. Stein, R. E. Dinnebier and V. Tomisic,
Chem. Eur. J., 2012, 18, 5620–5631.
2
, 935–939.
41 For the enol-imine form Schiff bases, the following values
-
1
(cm ) in literature are reported (ns= neat solid): a) C=N [
1641 (ns, ref 22), 1627–1614 (ref 19), 1607–1606 (KBr, ref
26, 18), 1554 (KBr, ref 26); b) O-H [ ] 3441–3316 (ref 19),
2996 (ns, ref 22), 2441–2434 (KBr, ref 26), [ ] 1388–1381 (ns,
ref 22), 1388–1374 (KBr, ref 18), [γo-o-p] 839–838 (KBr, ref
ν]
,
3
ν
2
2
δ
18), 809 (ns, ref 22); c) C-O [
1324 (KBr, ref 18).
ν] 1343–1327 (ns, ref 22), 1327–
2
-1
2
2
3
3
c) G. M. Sheldrick, Acta Cryst., 1990, A46, 467–473; d) G. M. 44 Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B.
Sheldrick, SHELX-TL version 5.03, Software Package for the
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
This journal is © The Royal Society of Chemistry 2018
New J. Chem., 2018, 42| 9
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 10 of 11
View Article Online
DOI: 10.1039/C7NJ04597B
Paper
Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H.
NJC
Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J.
E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K.
N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A.
Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski
and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
4
4
4
4
5 a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652; b) C.
Lee, W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785–789.
6 Y. Zhao and D. G. Truhlar, J. Phys. Chem., 2006, 110, 5121–
5
129.
7 T. Yanai, D. Tew and N. Handy, Chem. Phys. Lett., 2004, 393
1–57.
8 a) J. P. Perdew, K. Burke and M. Ernzerhof, Phys. Rev. Lett.,
996, 77, 3865–3868; b) J. P. Perdew, K. Burke and M.
,
5
1
Ernzerhof, Phys. Rev. Lett., 1997, 78, 1396; c) C. Adamo and
V. Barone, J. Chem. Phys., 1999, 110, 6158–6169.
9 J.-D. Chai and M. Head-Gordon, Phys. Chem. Chem. Phys.,
4
2
008, 10, 6615–6620.
0 J. P. Perdew, Phys. Rev. B, 1986, 33, 8822–8824.
1 A. D. Boese and J. M. L. Martin, J. Chem. Phys., 2004, 121
405–3416.
2 T. H. Dunning Jr. and P. J. Hay, in Modern Theoretical
Chemistry, Ed. H. F. Schaefer III, (Plenum, New York, 1976,
–28.
3 R. S. Mulliken, J. Chem. Phys., 1955, 23, 1833–1840.
5
5
,
3
5
3,
1
5
5
4 NBO Version 3.1, E. D. Glendening, A. E. Reed, J. E.
Carpenter, F. Weinhold, Gaussian Link 607.
5
5
5 C. M. Breneman and K. B. Wiberg, J. Comp. Chem., 1990, 11
61–373.
6 a) B. H. Besler, K. M. Jr. Merz and P. A. Kollman, J. Comp.
Chem., 1990, 11, 431–439; b) U. C. Singh and P. A. Kollman, J.
,
3
Comp. Chem., 1984,
7 R. Koster, M. Anderson and E. J. De Beer, Fed. Proc., 1959,
, 418–420.
5, 129–145.
5
18
1
0 | New J. Chem., 2018, 42
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 11 of 11
New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ04597B
Enantiopure Schiff bases of aminoacid phenylhydrazides: impact of the hydrazide function on
their structure and properties
Nadia Bouzayani, Sylvain Marque, Brahim Djelassi, Yakdhane Kacem, Jérôme Marrot and Béchir Ben Hassine
A new chiral Schiff bases have been synthesized and characterized with an important contribution of quantum
chemical calculations at a DFT level of theory. They have been evaluated for their physical and biological
properties.
The article was first published on date
New J. Chem., 2018, 42, Paper