Bis(Substituted Phenylamino)Glyoxime derivatives: Synthesis, characterization, and antimicrobial evaluation

Article abstract of DOI:10.1016/j.molstruc.2021.130812

In present work, a set of bis(substituted phenylamino) glyoxime derivatives are presented by the dropwise addition of corresponding primary aryl amines to the dichloroglyoxime (1). Reactions of corresponding primary aryl amines containing various substituents in different positions with dichloroglyoxime (1) gave thirteen compounds. The structural characterization of a set of bis(substituted phenylamino) glyoxime derivatives have been performed on the basis of FTIR, mass, proton, and carbon NMR methods. The crystal structure of compound 3a has been determined by X-ray diffraction on a single crystal. The NMR spectrum and X-ray data of 3a show that two hydroxyl groups of dioxime situated at anti position. Furthermore, all of the synthesized compounds (3a-m) were tested for in vitro both antimicrobial activity. The minimal inhibitory concentrations (MICs) against 7 bacteria and 3 yeasts were also determined. Among them, compound 3f was the most potent compound against S. aureus with the value of MIC = 9.76 μg/mL for the antibacterial activity, in addition to this, compound 3i has a good potency against S. aureus and C. tropicalis (MIC = 78.12 μg/mL) for both antibacterial and antifungal activities, respectively.

Full text of DOI:10.1016/j.molstruc.2021.130812

Journal of Molecular Structure 1242 (2021) 130812
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Bis(Substituted Phenylamino)Glyoxime derivatives: Synthesis,
characterization, and antimicrobial evaluation
Amaç Fatih Tuyuna,∗, Nilüfer Bayrakb, Hatice Yıldırımb, Mahmut Yıldızc,
Emel Mataracı-Karad, Berna Ozbek-Celikd
a Chemistry Department, Faculty of Science, Istanbul University, Fatih, Istanbul, Turkey
b Chemistry Department, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320, Istanbul, Turkey
c Chemistry Department, Gebze Technical University, Gebze, 41400, Kocaeli, Turkey
d Pharmaceutical Microbiology Department, Pharmacy Faculty, Istanbul University, Beyazit, 34116, Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In present work, a set of bis(substituted phenylamino) glyoxime derivatives are presented by the drop-
wise addition of corresponding primary aryl amines to the dichloroglyoxime (1). Reactions of correspond-
ing primary aryl amines containing various substituents in different positions with dichloroglyoxime (1)
gave thirteen compounds. The structural characterization of a set of bis(substituted phenylamino) gly-
oxime derivatives have been performed on the basis of FTIR, mass, proton, and carbon NMR methods.
The crystal structure of compound 3a has been determined by X-ray diffraction on a single crystal. The
NMR spectrum and X-ray data of 3a show that two hydroxyl groups of dioxime situated at anti posi-
tion. Furthermore, all of the synthesized compounds (3a-m) were tested for in vitro both antimicrobial
activity. The minimal inhibitory concentrations (MICs) against 7 bacteria and 3 yeasts were also deter-
mined. Among them, compound 3f was the most potent compound against S. aureus with the value of
MIC = 9.76 μg/mL for the antibacterial activity, in addition to this, compound 3i has a good potency
against S. aureus and C. tropicalis (MIC = 78.12 μg/mL) for both antibacterial and antifungal activities,
respectively.
Received 3 April 2021
Revised 25 May 2021
Accepted 28 May 2021
Available online 2 June 2021
Keywords:
Glyoxime
Oxime
vic-Dioximes
Antibacterial activity
Antifungal activity
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
their complexes with different metal ions have been obtained and
their extraction features were searched by solvent extraction. [11,
It has been a long time recognized that the vic-dioximes are the
important class of amongst the organic compounds having highly
versatile applications in a variety of fields, for instance, medicine
and bioinorganic chemistry. [1-3] Since the reaction of dimethyl-
glyoxime with Ni(II) was reported for the first time, the com-
plexation studies of these derivatives have been extensively stud-
ied comprehensively by a number of scientists due to their uti-
lization as catalysts in chemical processes, biological model com-
pounds such as vitamin B12, and analytical reagents. [4-10] An-
other good example of an application based on the vic-dioximes is
relevant to environmental perspectives. To develop an efficacious
extractant that has a considerable influence, especially in the ex-
traction process, on the separation and extraction efficiency used
for the removal, separation, and concentration of metal ions from
aqueous solutions, vic-dioximes are highly useful synthon. For this
purpose, many vic-dioximes possessing different substituents and
12]
Oximes and their derivatives, which are frequently used in or-
ganic synthesis, have a functional role as intermediates in the
preparation of various heterocyclic compounds. [15] Compounds
of vic-dioxime with two substituents (R-NH-) in 1,2-positions are
among the most attractive precursors that are used to synthesize
(hetero)cyclic compounds. [13] vic-Dioximes with two substituents
(R-NH-) in 1,2-positions containing two carbonyl functional groups,
play an important role in many areas. [14, 15] Given the unique
chemical and structural properties of those compounds, they have
been extensively investigated and applied in material science and
medicinal chemistry. [15] Vic-dioximes containing slightly acidic
hydroxy groups and slightly basic azomethine groups are ampho-
teric chelates that can form complexes of various types such as
square-pyramidal and octahedral with transition metal ions [14].
The investigation of their coordination chemistry has been exceed-
ingly amplified for different purposes mentioned above. [14, 16-19]
Additionally, there are some important reports concerning antimi-
crobial activities of bis(substituted phenylamino)glyoxime deriva-
∗
Corresponding author.
E-mail addresses: aftuyun@gmail.com, aftuyun@istanbul.edu.tr (A.F. Tuyun).
https://doi.org/10.1016/j.molstruc.2021.130812
0022-2860/© 2021 Elsevier B.V. All rights reserved.

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
Table 1
tives and their complexes in the literature. [20-22] It has sparked
interest in the exploration of their activities in bacteria and fungi,
two main types of pathogenic organisms, causing infectious dis-
eases that are one of the ten main reasons for mortality in the
world. [23] What is currently the most needed is to make an ef-
ficient search for candidates to be assayed as antibacterial agents
and highlight the role of organic compounds with a specific skele-
tons in their activities that have not been explored. Therefore, for a
better understanding of antimicrobial properties of bis(substituted
phenylamino)glyoxime compounds, this study is going to be a pre-
liminary investigation for the synthesis of new derivatives and this
will open the attractive perspectives for the design of new antimi-
crobial agents containing vic-dioximes.
Crystallographic data for the 3a.
Identification code
Chemical formula
Formula weight (g mol−1
3a
C
16H18N4O4
)
330.346
Temperature (K)
273.15
˚
Radiation λ (A)
0.71073
Crystal system
Orthorhombic
P212121, 4
Space groups, Z 4
˚
Unit cell dimensions (A)
a = 7.1630(15)
b = 15.071(4)
c = 15.305(3)
α, β, γ = 90°
1652.3(6)
3
˚
Volume (A )
Crystal sizes (mm)
0.214 × 0.178 × 0.138
1.328
dcalc (g cm−3
Absorption coefficient (mm−1
Absorption correction, Tmin, Tmax
max, deg
)
The first aim of this work is to prepare novel bis(substituted
phenylamino)glyoximes (3a-m) via the reaction of primary aryl
amines with various substituents in different positions and
dichloroglyoxime (1). The second aim is to confirm their structures
by spectral data obtained X-ray single crystal, FTIR, NMR, and Mass
spectrometers. The third aim is to understand their potential for
antimicrobial properties as well.
)
0.098
none, 0.979, 0.987
25.010
θ
Goodness-of-fit on F2
1.045
Index ranges
-8 ≤ h ≤ 8,
-17 ≤ k ≤ 17,
-18 ≤ l ≤ 10
6890
Reflections collected
Independent reflections
Final R indices [I > 2σ(I)]
2872 [Rint = 0.0351, Rsigma = 0.0524]
R1 = 0.0431,
wR2 = 0.0925
R1 = 0.0658,
wR2 = 0.1038
’\f and \w scans’
2872/0/228
2. Materials and methods
R indices (all data)
Refinement method
2.1. Materials and general techniques
Data/restraints/parameters
−3
˚
Largest diff. peak and hole (eA
)
0.18/-0.19
General experimental method: All reactions were carried out
in oven-dried glassware. The starting material dichloroglyoxime (1)
for this research was prepared as reported previously. [24]
Reagents and solvents: All reagents used in the reactions and
organic solvents used in the purification step were purchased from
commercially available sources and they were used as sold.
Chromatography: Thin layer chromatography (TLC) was applied
to monitor the reactions by using Merck silica gel 60 F254 plates
and visualized by fluorescence quenching under UV light (254 nm).
Melting points: Melting points (mp) were obtained on a Buchi
B-540 melting point without being corrected.
Table 2
˚
Selected bond lengths (A) with e.s.d (in paren-
theses) for 3a.
3a
O2-N1
O3-N2
O4-C15
O4-C16
N1-C8
N2-C9
N4-C8
N4-C7
O1-C2
O1-C1
N3-C9
N3-C10
C8-C9
C7-C2
C7-C6
1.426(3)
1.416(2)
1.357(3)
1.422(3)
1.284(3)
1.289(3)
1.360(3)
1.410(3)
1.360(3)
1.419(4)
1.359(3)
1.415(3)
1.482(3)
1.384(3)
1.381(4)
C10-C15
C10-C11
C2-C3
1.392(4)
1.373(4)
1.379(4)
1.385(4)
1.387(4)
1.384(3)
1.381(4)
1.370(5)
1.372(4)
1.377(5)
1.363(5)
1.381(4)
1.370(5)
1.372(4)
1.377(5)
C15-C14
C11-C12
C7-C2
Mass spectra: Mass spectra were measured in ESI mode on
C6-C5
C14-C13
C12-C13
C3-C4
a
Thermo Finnigan LCQ Advantage MAX MS/MS spectrometer
equipped or a BRUKER Microflex LT by MALDI-TOF technique via
the addition of 1,8,9-anthracenetriol (DIT, dithranol) as matrix.
Infrared spectra: Infrared spectra were measured on Thermo
Scientific Nicolet 6700 spectrometer or Alpha T FTIR spectrometer,
and ATR on a Perkin Elmer Spectrum 100 Optical FT-IR Spectrom-
eter.
C5-C4
C6-C5
C14-C13
C12-C13
C3-C4
NMR spectra: NMR spectra were recorded in DMSO-d6 on a
VarianUNITY INOVA spectrometer (500 MHz frequency for 1H and
125 MHz frequency for 13C NMR) in ppm. The coupling constants J
are given in Hz.
2.2. Experimental procedures, analytical, and spectroscopic data
X-Ray Diffraction Analysis: Data for the single crystal com-
pound were obtained with Bruker APEX II QUAZAR three-circle
diffractometer. Crystal structure validations and geometrical cal-
culations were performed using the Platon software. [25] Mer-
cury software [26] was used for visualization of the .cif files. The
structure has been solved by the Bruker SHELXTL Software Pack-
age and refined using OLEX2.refine. [27, 28] The software used for
molecular graphics: OLEX2 1.3 [29]; to prepare material for publi-
cation: OLEX2 1.3. [29] Data integration and reduction were carried
out with SAINT. [30] The crystallographic and structure refinement
data are summarized in Table 1. The selected bond lengths, torsion
angles, bond angles, and hydrogen-bonding geometry are given in
Tables 2-5. The crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre, and CCDC reference num-
ber is 2072528 for 3a. The data can be obtained available free of
charge from http://www.ccdc.cam.ac.uk/conts/retrieving.html.
2.2.1. Nucleophilic reaction between dichloroglyoxime and substituted
aryl amines
General procedure.
Primary aryl amine (2.2 equiv.) in 3 mL ethanol was added
into two necked RB flask that contained a solution of dichloro-
glyoxime (0.393 g, 2.5 mmol) in 3 mL ethanol (-10 °C). After tri-
ethylamine was added, the reaction was allowed to proceed with
continued stirring of the solution at room temperature by the time
TLC showed the absence of the starting materials (3-4 hours). The
resultant solid was gathered by vacuum filtration to give the prod-
ucts (3a-m).
N1’,N2’-Dihydroxy-N1,N2-bis(2-methoxyphenyl)oxalamidine (3a).
It was synthesized from dichloroglyoxime (1) and 2-
methoxybenzenamine (2a) as cream powder according to the
general procedure. Yield: 0.63 g, 76%. IR and 1H NMR spectra
were found to be identical with the ones described in literature.
2

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
(s, 2H, -NH), 6.79 (d, J: 8.8 Hz, 2H, Ar-H), 6.40 (d, J: 2.5 Hz, 2H,
Ar-H), 6.35 (dd, J: 8.8, 2.5 Hz, 2H, Ar-H), 3.68 (s, 6H, -OCH3), 3.63
(s, 6H, -OCH3) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 155.8,
150.3, 143.4, 121.7, 119.4, 104.4, 99.0, 56.0, 55.7 ppm; MS MALDI
TOF: (m/z) = 390 (M)+, Exact Mass for C18 H22N4O6 (390.15).
N1’,N2’-Dihydroxy-N1,N2-bis(3,4,5-trimethoxyphenyl)oxalamidine
(3g).
[31] FTIR (ATR): υ
= 3400, 3296, 3067, 3022, 2952, 2833, 1655,
1621, 1597, 1512, 958, 927 cm−1 1H NMR (500 MHz, DMSO-d6):
;
δ = 10.75 (s, 2H, -OH), 7.53 (s, 2H, -NH), 6.87-6.83 (m, 6H, Ar-H),
6.77-6.73 (m, 2H, Ar-H), 3.70 (s, 6H, -OCH3) ppm; 13C NMR (125
MHz, DMSO-d6): δ = 148.5, 142.4, 128.2, 122.3, 120.9, 117.2, 111.2,
56.1 ppm; MS MALDI TOF: (m/z) = 331 (M+H)+, Exact Mass. for
C16 H18 N4O4 (330.13).
N1’,N2’-Dihydroxy-N1,N2-bis(4-methoxyphenyl)oxalamidine (3b).
It was synthesized from dichloroglyoxime (1) and 4-
methoxybenzenamine (2b) as light pink powder according to
the general procedure. Yield: 0.53 g, 64%. IR and 1H NMR spectra
were found to be identical with the ones described in literature.
It was synthesized from dichloroglyoxime (1) and 3,4,5-
trimethoxybenzenamine (2g) as white powder according to the
general procedure. Yield: 0.48 g, 40%; M.p: 211-212 °C. FTIR (ATR):
υ
= 3407, 3348, 2978, 2944, 2848, 2822, 1653, 1631, 1594, 940,
918 cm−1
;
1H NMR (500 MHz, DMSO-d6): δ = 10.34 (s, 2H, -OH),
7.98 (s, 2H, -NH), 6.13 (s, 4H, Ar-H), 3.60 (s, 12H, -OCH3), 3.56 (s,
6H, -OCH3) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 152.7, 144.0,
136.0, 133.0, 98.3, 60.6, 55.9 ppm; MS MALDI TOF: (m/z) = 451
(M+H)+, Exact Mass for C20H26N4O8 (450.18).
[32] FTIR (ATR): υ
= 3344, 3278, 3011, 2956, 2930, 2833,
1H NMR (500 MHz, DMSO-d6): δ = 10.15
1660, 1628, 934 cm−1
;
(s, 2H, -OH), 7.82 (s, 2H, -NH), 6.71 (d, J: 9.2 Hz, 4H, -OCH2), 6.67
(d, J: 9.2 Hz, 4H, -OCH2), 3.67 (s, 6H, -OCH3) ppm; 13C NMR (125
MHz, DMSO-d6): δ = 155.0, 143.9, 133.4, 121.8, 114.0, 55.6 ppm;
MS MALDI TOF: (m/z) = 330 (M)+, Exact Mass for C16 H18 N4O4
(330.13).
N1,N2-Bis(2-ethoxyphenyl)-N1’,N2’-dihydroxyoxalamidine (3c).
It was synthesized from dichloroglyoxime (1) and 2-
ethoxybenzenamine (2c) as cream powder according to the
general procedure. Yield: 0.48 g, 53%; M.p: 205-206 °C. FTIR
N1,N2-Bis(2,5-diethoxyphenyl)-N1’,N2’-dihydroxyoxalamidine (3h).
It was synthesized from dichloroglyoxime (1) and 2,5-
diethoxybenzenamine (2h) as black powder according to the gen-
eral procedure. Yield: 0.77 g, 76%; M.p: 137-138 °C. FTIR (ATR): υ
= 3393, 3232, 3096, 2980, 2937, 2878, 1598, 931 cm−1
;
1H NMR
(500 MHz, DMSO-d6): δ = 10.88 (s, 2H, -OH), 7.61 (s, 2H, -NH), 6.71
(d, J: 8.8 Hz, 2H, Ar-H), 6.51 (d, J: 2.5 Hz, 2H, -Ar-H), 6.32 (dd, J:
8.8, 2.5 Hz, 2H, Ar-H), 3.95-3.75 (m, 8H, -OCH2), 1.38-1.30 (m, 12H,
-CH3) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 153.0, 142.3, 141.5,
129.1, 113.7, 107.0, 103.8, 65.1, 63.4, 15.2, 15.1 ppm; MS MALDI TOF:
(m/z) = 447 (M+H)+, Exact Mass for C22H30N4O6 (446.22).
N1,N2-Di(benzo [d] [1,3]dioxol-5-yl)-N1’,N2’-dihydroxyoxalamidine
(3i).
(ATR):
υ = 3376, 3240, 2979, 2903, 1625, 1510, 934 cm−1
;
1H
NMR (500 MHz, DMSO-d6): δ = 10.75 (s, 2H, -OH), 7.54 (s, 2H,
-NH), 6.88-6.84 (m, 2H, Ar-H), 6.82-6.79 (m, 4H, Ar-H), 6.77-6.71
(m, 2H, Ar-H), 3.89 (q, J: 6.9 Hz, 4H, -OCH2), 1.29 (t, J: 6.9 Hz, 6H,
-CH3) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 147.6, 142.4, 128.4,
122.2, 120.8, 117.1, 112.3, 64.3, 15.1 ppm; MS (ESI+): m/z (%) = 359
(100, (M+H)+), Exact Mass for C18 H22N4O4 (358.16).
It was synthesized from dichloroglyoxime (1) and 3,4-
(methylenedioxy)aniline (2i) as grey powder according to the gen-
eral procedure. Yield: 0.77 g, 86%; M.p: 210 °C. FTIR (ATR): υ
N1,N2-Bis(4-ethoxyphenyl)-N1’,N2’-dihydroxyoxalamidine (3d).
It was synthesized from dichloroglyoxime (1) and 4-
ethoxybenzenamine (2d) as off-white powder according to
the general procedure. Yield: 0.58 g, 81%; M.p: 169 °C. FTIR (ATR):
= 3374, 3178, 3115, 2893, 2793, 1630, 1487, 1435, 928 cm−1
;
1H NMR (500 MHz, DMSO-d6): δ = 10.26 (s, 2H, -OH), 7.95 (s, 2H,
-NH), 6.64 (d, J: 8.3 Hz, 2H, Ar-H), 6.37 (d, J: 2.2 Hz, 2H, Ar-H),
6.25 (dd, J: 8.3, 2.2 Hz, 2H, Ar-H), 5.90 (s, 4H, -OCH2) ppm; 13C
NMR (125 MHz, DMSO-d6): δ = 147.3, 143.8, 142.6, 134.7, 113.0,
108.0, 102.6, 101.1 ppm; MS MALDI TOF: (m/z) = 359 (M+H)+, Ex-
act Mass for C16 H14 N4O6 (358.09).
υ
= 3371, 3173, 3060, 2975, 2930, 2885, 2811, 1636, 1619,
969, 921 cm−1
.
1H NMR (500 MHz, DMSO-d6): δ = 10.14 (s, 2H,
-OH), 7.81 (s, 2H, -NH), 6.69 (d, J: 9.2 Hz, 4H, -OCH2), 6.65 (d, J:
9.2 Hz, 4H, -OCH2), 3.92 (q, J: 6.9 Hz, 4H, -OCH2), 1.28 (t, J: 6.9 Hz,
6H, -CH3) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 154.2, 143.9,
133.3, 121.8, 114.5, 63.5, 15.2 ppm; MS MALDI TOF: (m/z) = 358
(M)+, Exact Mass for C18 H22N4O4 (358.16).
N1-(2,3-Dihydrobenzo
[b]
[1,4]dioxin-6-yl)-N2-(2,3-
dihydrobenzo [b] [1,4]dioxin-7-yl)-N1’,N2’-dihydroxyoxalamidine
(3j).
N1,N2-Bis(4-butoxyphenyl)-N1’,N2’-dihydroxyoxalamidine (3e).
It was synthesized from dichloroglyoxime (1) and 4-
butoxybenzenamine (2e) as off-green powder according to the
general procedure. Yield: 0.29 g, 91%; M.p: 136-137 °C. FTIR (ATR):
It was synthesized from dichloroglyoxime (1) and 1,4-
benzodioxan-6-amine (2j) as cream powder according to the gen-
eral procedure. Yield: 0.62 g, 64%; M.p: 141-142 °C. FTIR (ATR): υ
= 3667, 3341, 3202, 2979, 2904, 1607, 1506, 1062, 888 cm−1
;
1H
υ
= 3366, 3189, 2972, 2905, 1646, 1620, 1509, 890 cm−1
;
1H
NMR (500 MHz, DMSO-d6): δ = 10.20 (s, 2H, -OH), 7.87 (s, 2H, -
NH), 6.58-6.56 (m, 2H, Ar-H), 6.38-6.31 (m, 4H, -ArH), 4.17-4.12 (m,
8H, -OCH2CH2O-) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 143.6,
143.2, 138.9, 134.0, 116.7, 113.4, 109.3, 64.7, 64.2 ppm; MS (ESI+):
m/z (%) = 387 (100, (M+H)+), Exact Mass for C18 H18 N4O6 (386.12).
N1’,N2’-Dihydroxy-N1,N2-bis(2-isopropylphenyl)oxalamidine (3k).
It was synthesized from dichloroglyoxime (1) and 2-
isopropylbenzenamine (2k) as brown powder according to the
general procedure. Yield: 0.57 g, 64%; M.p: 166-167 °C. FTIR (ATR):
NMR (500 MHz, DMSO-d6): δ = 10.14 (s, 2H, -OH), 7.80 (s, 2H,
-NH), 6.69 (d, J: 9.2 Hz, 4H, -OCH2), 6.65 (d, J: 9.2 Hz, 4H, -OCH2),
3.86 (t, J: 6.5 Hz, 4H, -OCH2), 1.68-1.62 (m, 4H, -CH2), 1.46-1.38
(m, 4H, -CH2), 0.92 (t, J: 7.32 Hz, 6H, -CH3) ppm; 13C NMR (125
MHz, DMSO-d6): δ = 154.4, 143.9, 133.3, 121.8, 114.5, 67.7, 31.3,
19.2, 14.2 ppm; MS (ESI+): m/z (%) = 415 (100, (M+H)+), Exact
Mass for C22H30N4O4 (414.23).
N1’,N2’-Dihydroxy-N1,N2-bis(2,4-dimethoxyphenyl)oxalamidine
(3f).
υ
= 3667, 3404, 3071, 3170, 2966, 2905, 1643, 1596, 947
1H NMR (500 MHz, DMSO-d6): δ = 10.65 (s, 2H, -OH),
It was synthesized from dichloroglyoxime (1) and 2,4-
dimethoxybenzenamine (2f) as brown powder according to the
general procedure. Yield: 0.78 g, 80%; M.p: 170 °C. FTIR (ATR):
cm−1
;
7.06-6.92 (m, 10H, Ar-H and NH), 2.50-2.43 (m, 2H, -CH), 0.84
(d, J: 6.8 Hz, 12H, -CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
δ = 144.2, 139.0, 136.3, 125.7, 123.8, 121.2, 115.2, 27.0, 22.9 ppm;
υ
= 3404, 3299, 3015, 2959, 2833, 1653, 1616, 1596, 955, 940
1H NMR (500 MHz, DMSO-d6): δ = 10.45 (s, 2H, -OH), 7.11
cm−1
;
3

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
MS (ESI+): m/z (%) = 354 (100, (M)+), Exact Mass for C20H26N4O2
(354.21).
N1’,N2’-Dihydroxy-N1,N2-bis(4-isopropylphenyl)oxalamidine (3l).
It was synthesized from dichloroglyoxime (1) and 4-
isopropylbenzenamine (2l) as light brown powder according
to the general procedure. Yield: 0.7 g, 79%; M.p: 116-118 °C. FTIR
step, we have used N-Chlorosuccinimide in portions for chlorina-
tion of glyoxime in order to obtain dichloroglyoxime (1) in DMF
at -10 °C as reported earlier. [24] Thirteen different bis(substituted
phenylamino) glyoxime compounds (3a-m) have been synthe-
sized which are examples of substituted vic-dioximes and sum-
marized in Scheme 2. These derivatives were obtained according
to the literature by the reactions of a wide range of primary aryl
amines bearing divergent substituents with dichloroglyoxime (1)
in ethanol at -10 °C. In most cases, the products obtained were
solid in good yields and could be collected by filtration as the only
purification method. 1H and 13C NMR, FTIR, and MS spectral data
were used to determine the structures of these new compounds
given in the Experimental Section.
(ATR): υ
= 3667, 3380, 3179, 2964, 2905, 1604, 1512, 1056,
1H NMR (500 MHz, DMSO-d6): δ = 10.31 (s, 2H, -OH),
950 cm−1
;
8.01 (s, 2H, -NH), 6.93 (d, J: 8.5 Hz, 4H, Ar-H), 6.73 (d, J: 8.6 Hz,
4H, Ar-H), 2.76 (p, J: 6.8 Hz, 2H, -CH), 1.14 (d, J: 6.8 Hz, 12H, -CH3)
ppm. 13C NMR (125 MHz, DMSO-d6): δ = 143.3, 141.8, 137.9, 126.5,
126.3, 119.7, 33.2, 33.0, 24.5, 24.4 ppm; MS (ESI+): m/z (%) = 355
(100, (M+H)+), Exact Mass for C20H26N4O2 (354.21).
FTIR data provide evidence for principal functional groups on
the structure of the bis(substituted phenylamino)glyoxime deriva-
tives (3a-m). Some of the characteristic bands such as OH and NH
vibrations have been observed for these compounds. [17] In the
FTIR spectral data of the synthesized compounds in this paper, the
bands at expected areas pertain to N-H and O-H stretching vibra-
tions, respectively, agreeing with previously reported values of the
substituted vic-dioximes. [18]
N1,N2-Bis(4-(diethylamino)phenyl)-N1’,N2’-dihydroxyoxalamidine
(3m).
It was synthesized from dichloroglyoxime (1) and 4-
diethylamino benzenamine (2m) as off-white powder according to
the general procedure. Yield: 0.99 g, 95%; M.p: 209 °C. FTIR (ATR):
υ
= 3304, 3107, 2974, 2704, 1643, 944 cm−1
;
1H NMR (500
MHz, DMSO-d6): δ = 9.96 (s, 2H, -OH), 7.53 (s, 2H, -NH), 6.66 (d,
J: 9.0 Hz, 4H, Ar-H), 6.44 (d, J: 9.0 Hz, 4H, Ar-H), 3.23 (q, J: 6.8
Hz, 8H, Ar-H), 1.03 (t, J: 6.8 Hz, 12H, -CH3) ppm; 13C NMR (125
MHz, DMSO-d6): δ(ppm) = 144.5, 143.9, 129.3, 122.5, 112.6, 44.4,
12.8 ppm; MS MALDI TOF: (m/z) = 410 (M-2H)+, Exact Mass for
C22H32N6O2 (412.26).
Additional structural information can be deduced from both
proton and carbon NMR spectra. The structures of 3a-m are fur-
ther confirmed by the study of proton magnetic resonance spectra
in dimethyl sulfoxide-d6 in which the hydroxyl and amine protons
of these compounds resonated as two singlets at very similar val-
ues around 10.5 and 7.5 ppm, respectively. The aromatic protons
of phenylamino moiety were observed at between 6.5-7.5 ppm.
The proton-decoupled 13C NMR spectral data were also in harmony
with the structure of 3a-m. The chemical shifts belong to the sub-
stituents on the aryl ring; methoxy, ethoxy, butoxy, i-propyl, N,N-
diethyl, methylenedioxy, and ethylenedioxy derivatives were as ex-
pected in the 13C NMR spectra of molecules. Assignment of the ex-
changeable protons of bis(substituted phenylamino)glyoxime was
confirmed based on data from D2O exchange, after the exchange-
able protons peaks have clearly disappeared or decreased in inten-
sity. From the present mass spectral data, it is concluded molecular
ion peaks of glyoxime derivatives, which confirmed the proposed
structures.
2.3. In vitro antimicrobial activity
2.3.1. Determination of Minimum Inhibitory Concentrations (MIC)
The microbroth dilutions technique was performed to deter-
mine antimicrobial activity against Staphylococcus aureus ATCC
29213, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC
25922, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa
ATCC 27853, Proteus mirabilis ATCC 14153, Enterococcus faecalis
ATCC 29212, Candida albicans ATCC 10231, Candida parapsilosis
ATCC 22019, and Candida tropicalis ATCC 750 according to the Clin-
ical Laboratory Standards Institute (CLSI) recommendations. [33,
34] Mueller-Hinton broth for bacteria and RPMI-1640 medium for
yeast strain were used as the test medium. Serial twofold dilu-
tions ranging from 2500 μg/mL to 4.88 μg/mL were prepared in the
medium. The inoculum was prepared using a 4-6 h broth culture
of each bacteria type and 24 h culture of yeast strains adjusted to
a turbidity equivalent to 0.5 McFarland standard, diluted in broth
media to give a final concentration of 5 × 105 cfu/mL for bacteria
and 5 × 103 cfu/mL for yeast in the test tray. The trays were cov-
ered and placed into plastic bags to prevent evaporation. The trays
containing Mueller-Hinton broth were incubated at 35°C for 18-20
h while the trays containing RPMI-1640 medium were incubated
at 35°C for 46–50 h. The MIC was defined as the lowest concen-
tration of compound giving complete inhibition of visible growth.
As a control, antimicrobial effects of the solvents were investigated
against test microorganisms. According to the values of the con-
trols, the results were evaluated. The MIC values of the compounds
are shown in Table 6.
NMR spectra of the bis(substituted phenylamino)glyoxime com-
pounds (3a-m) were taken first for structure determination.
Bis(substituted phenylamino)glyoxime structure has NH and OH
groups. The peaks around 9.5-10.5 ppm and 7.5-8.0 ppm belonged
to the N-OH and NH group protons at 1H NMR. As proof, when
taken the D2O exchange spectra of them, these peaks were dis-
appeared. The compounds 3b, 3d, 3e, 3l, and 3m had a common
splitting pattern of two para-substituted rings in the aromatic re-
gion. Looked at the 1H NMR of 3l and 3, in the aromatic region,
two doublet patterns were seen at around 6.93, and 6.73 ppm with
Jortho 8.5 Hz for 3l and 6.66 ppm and 6.44 ppm with Jortho 9.0
Hz for 3m (Figure 1a). However, for the compound 3b, 3d, and
3e these two doublets were too close to each other at 6.69 ppm
(Jortho 9.2) Hz) and 6.65 ppm (Jortho 9.2 Hz) (Figure 1b). In the 1H
NMR spectra of 3f, 3h, and 3i, there were three splitting patterns
of aromatic protons. It can be seen Jortho and Jmeta values for these
structures. Proton Ha has no neighboring proton so it was just split
by meta proton Hb as a doublet pattern with Jmeta value around
2.5 Hz. Proton Hb was split by ortho proton Hc and meta proton
Ha as a doublet of doublets (dd) pattern with Jortho and Jmeta val-
ues around 8.8 Hz and 2.5 Hz, respectively. Looked at proton Hc,
it can be determined easily it was split by neighboring proton Hb
as a doublet pattern with Jortho value around 8.8 Hz (Figure 1c).
In the 13C NMR spectrum, the two symmetrically carbon of gly-
oxime backbone (C=NOH) were seen at around 156-143 ppm. The
structure 3g showed only two peaks of Carom-OMe at around 144
and 136 ppm because of the symmetry even though it has three
3. Results and discussion
3.1. Chemistry
The starting material dichloroglyoxime (1) for this study was
prepared as reported previously, following a modified method of
van der Peet shown in Scheme 1. [24] The glyoxal (40% w/v)
was reacted with hydroxylamine hydrochloride in the presence of
triethylamine to prepare glyoxime in water at -10 °C. After this
4

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
(a)
(b)
(c)
Fig; 1. The splitting patterns of substituted phenyl groups.
methoxy groups (OMe). The carbons (=CH) of para-alkoxy substi-
tuted phenyl groups were at around 113 and 122 ppm at 13C NMR.
When looked at the carbons (=CH) peaks of ortho-alkoxy substi-
tuted phenyl, the signals were seen at around 122, 120, 117, and
112 ppm as four peaks.
3.2. X-ray crystallographic analysis
An x-ray diffraction structural study was carried out on
bis(substituted phenylamino)glyoxime on an automatic diffrac-
tometer using λ MoK radiation using 6890 reflections. The struc-
ture of 3a was confirmed by X-ray diffraction analysis of a sin-
gle crystal obtained by slow evaporation from an ethyl alcohol so-
lution. The unit cell parameters of the crystal of 3a compound,
C16 H18 N4O4 at 273 K, which has three axes of different lengths
(a = 7.1630, b = 15.071, c = 15.305) and whose axes intersect at 90
degrees (α, β, γ = 90°) with space groups P212121, is compatible
to ortothorhombic crystal system. In the X-Ray study, it is deter-
mined that the structure of 3a has anti configurations of the oxime
groups in symmetrically substituted glyoxime compound. The bond
˚
˚
˚
lengths of C8 -C9 (1.482 A), N1-C8 (1.284 A), and N2-C9 (1.289 A)
in the structure of 3a are specific for glyoximes, featuring conju-
gation between the π systems (C=NOH) in the dioxime fragment.
[35] The length of the N4-C8 and N3-C9 bonds between the sp3
hybridized N and sp2 hybridized C atoms in compound 3a is about
2
˚
˚
1.360 A, which is greater than 1.28 A between the sp hybridized N
and the C atom of the disubstituted glyoxime compound. This is in
line with the rule that bonds between sp2-sp2 hybridized atoms
are shorter than bonds between sp2-sp3 hybridized atoms. The
lengths of the aromatic C-C bonds in the phenyl group range from
˚
1.363 to 1.402 A. The O1-C1 and O4-C16 bond lengths of methoxy
Fig. 2. ORTEP drawings of the 3a at 50% probability level.
˚
groups in the phenyl rings are 1.419 and 1.422 A, respectively. The
ORTEP drawing of the 3a was reported at a 50% probability level
in Figure 2. The crystallographic and structure refinement data for
compound 3a is summarized in Table 1. The molecular geometry
with bond lengths and angles in the dioxime fragment is given in
Tables 2 and 4. The C-C-C bond angles of the phenyl ring of 3a
are very close to 120.8o which supports structures involving sp2
hybridized atoms.
show that two OH groups are anti position. Moreover, the NMR
spectrum of 3a shows OH peaks as a singlet at 10.75 ppm and
this singlet peak proves the anti-configuration. [36] From the lit-
erature, this kind of isomeric structure is called anti (E,E). [14, 18,
37, 38] Some other torsion angles of compound 3a given in Table 3
support the structure. In terms of bond distances and angles, the
molecular geometry of 3a is compatible with the expected.
The torsion angle of two phenyl amino groups bonded to the
dioxime fragment is N4-C8-C9-N3 is -54.3 . Also, the dihedral an-
In the structure of 3a, there are hydrogen acceptor and donor
groups. Therefore, the x-ray data shows possible both intermolecu-
lar and intramolecular hydrogen bonds. The corresponding distance
and angle of hydrogen bonds are given in Table 5. All crystallo-
º
gle between two oxime groups (N1-C8-C9-N2) is -59.3 . The N1-
º
C8-C9-N3 and N2-C9-C8-N4 torsion angles are 124.0 and 122.4 ,
º
º
respectively. O2-N1-C8-NC9 (178.85 ) and O3-N2-C9-C8 (-179.15 )
º
º
5

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
graphic data of the compounds are presented in the supplemen-
tary material (Supplementary Material, SM).
3.3. Antimicrobial activity
All of the synthesized compounds (3a-m) were involved in a
study to evaluate for their in vitro antimicrobial activity by com-
paring Ceftazidime, Cefuroxime-Na, Cefuroxime, Amikacin, Clotri-
mazole, and Amphotericin B. Tested Gram-negative were P. aerugi-
6

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
Table 3
Torsion angles (°) for 3a.
3a
O2-N1-C8-C9
O2-N1-C8-N4
O3-N2-C9-C8
O3-N2-C9-N3
N1-C8-N4-C7
N2-C9-N3-C10
178.95(17)
−2.9(2)
N1-C8-C9-N3
N2-C9-C8-N4
N4-C7-C2-C3
O1-C2-C3-C4
N4-C8-C9-N3
O4-C15-C14-13
124.0 (2)
122.4(2)
179.7(3)
178.2(3)
−54.3(2)
178.9(3)
-179.15 (18)
-2.7 (2)
159.0(2)
171.6(2)
Table 4
Selected bond angles (°) for with e.s.d (in parentheses) for
3a.
3a
C16-O4-C15
C8-N1-O2
C9-N2-O3
C7-N4-C8
C1-O1-C2
C10-N3-C9
N4-C8-N1
C9-C8-N1
C9-C8-N4
N3-C9-N2
C8-C9-N2
C8-C9-N3
C2-C7-N4
C6-C7-N4
117.7(2)
109.81(18)
110.22(19)
125.2(2)
118.2(3)
125.3(2)
126.1(2)
114.6(2)
119.3(2)
125.3(2)
114.3(2)
120.4(2)
119.2(2)
121.3(2)
C6-C7-C2
119.4(3)
118.1(2)
119.9(2)
120.1(3)
125.5(3)
119.9(3)
114.6(2)
125.7(3)
119.5(3)
120.6(3)
120.2(3)
119.6(3)
120.2(3)
120.2(3)
C15-C10-N3
C11-C10-C15
C5-C4-C3
C3-C2-O1
C3-C2-C7
C7-C2-O1
C14-C15-O4
C14-C15-C10
C12-C11-C10
C5-C6-C7
C13-C14-C15
C4-C3-C2
C4-C5-C6
Table 5
˚
Hydrogen-bonding geometry (A, °) for 3a.
D-H…A
D-H
H…A
D…A
D-H…A
O2-H2…N1
O2-H2…N2
O3-H3…O2
N3-H3A…O3
0.90 (3)
2.56 (3)
1.93 (3)
1.984 (9)
2.247 (3)
3.132 (3)
2.804 (3)
2.783 (2)
2.572 (3)
122 (3)
163 (3)
165 (2)
102.4 (2)
0.90 (3)
0.820 (13)
0.860 (3)
nosa, E. coli, K. pneumoniae, and P. mirabilis, whereas Gram-positive
bacteria were S. aureus, S. epidermidis, and E. faecalis. The tested
fungi were C. albicans, C. parapsilosis, and C. tropicalis. The obtained
results reflected variable antimicrobial activity and are given in
Table 6.
Among the synthesized and tested compounds, compound 3f
had the best MIC value (MIC = 9.76 μg/mL) against S. aureus. In
addition, 3i showed good potency against S. aureus and C. trop-
icalis (MIC = 78.12 μg/mL). Both test-cultures S. epidermidis and
S. aureus appeared to be susceptible to most of the synthesized
compounds with MIC values of between 9.76–1250 μg/mL. The
test-cultures C. albicans showed not to be susceptible to all of the
synthesized compounds. The biological data also reveal that both
compounds 3f and 3i were the most active among the synthe-
sized compounds; they have both antibacterial and antifungal ac-
tivities. Although 3m did not show activity against fungi, it has
moderate activity against two important pathogen microorganisms
of the Gram-negative Enterobacteriaceae family (Klebsiella pneumo-
niae and Escherichia coli) and also Gram-positive microorganisms
(Staphylococcus aureus and Staphylococcus epidermidis).
3.4. Structure-Activity Relationship (SAR) study
When we analyzed the structural features with their MIC values
of the synthesized compounds by modification of various positions
in the aryl amine moiety, the obtained results from the antibacte-
rial activity are quite interesting because of the correlation against
S. aureus strains. When all molecules were analyzed against the
Gram-negative bacteria and the Gram-negative bacteria in addition
to fungi, it seems difficult to abstract definite structure-activity re-
7

A.F. Tuyun, N. Bayrak, H. Yıldırım et al.
Journal of Molecular Structure 1242 (2021) 130812
lationship except that S. aureus since there is not any sufficient
data. We noticed that there is no significant activity against the
rest of the microorganisms when we analyzed the effect of the
position and presence of the substituent(s) on the phenyl ring in
tested molecules. Among them, 3f containing two alkoxy groups on
the phenyl ring had the best antibacterial activity against S. aureus.
The two substituents in a cyclic structure (3i and 3j) was unfavor-
able in relation to the antibacterial activity against S. aureus when
compared with the 3f. Leading the loss of activity has been noticed
for the 3g containing the three alkoxy groups on the phenyl ring.
Thus, it may be concluded that the presence of two substituents, in
particular alkoxy groups, on the phenyl ring is vital for obtaining
good activity against S. aureus.
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The corresponding author is responsible for ensuring that the
descriptions are accurate and agreed by all authors.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
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