Azines: Synthesis, Structure, Electronic Structure and Their Applications

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ARTICLE
Azines: Synthesis, Structure, Electronic Structure and their

Applications
iReceived00th January 20xx, Sumit S. Chourasiya, Deepika Kathuria, Aabid Abdullah Wani and Prasad V. Bharatam*
Accepted 00th January 20xx
Azines are organic molecules which carry the C=N–N=C functional unit. In the recent past, azines received increased
DOI: 10.1039/x0xx00000x
attention due to the recognition of their biological, chemical and material properties. Azines are conventionally synthesised
by the condensation of hydrazine with ketones and aldehydes, many alternate routes are also available. The conjugation (or
lack of it) in azines was investigated with the help of computational studies and crystal structure analysis. The tautomerism
in azines is a topic of contemporary interest. Herein, we present a review of recent advances in the structure and electronic
structure properties of azines along with information on the modern methods of their synthesis and application as
precursors in generating heterocycles in organic synthesis and in medicinal chemistry. A few applications of azines in
generating covalent organic frameworks (COF), metal organic frameworks (MOF), energetic material and chemosensors are
also included.
1. Introduction
Azines are 2,3-diaza analogues of 1,3-butadiene and are
sometimes also referred as N—N linked diimines (C=N–N=C).1, 2 The Figure 1. Symmetrical azines (1,3) and unsymmetrical azines (2,4).
first example of azine is dimethylketazine which was synthesised by
Azines are receiving increasing attention for their
Curtius and Thun in 1891 from the reaction of two molecules of
biological, chemical and physical properties. This review deals
acetone with hydrazine.3 These compounds are conventionally with the alicyclic azines. These azines received much less
synthesised by the condensation of hydrazine with attention in chemistry due to two factors – (i) Predominance of
aldehydes/ketones.4 With the recent advances in the chemistry, the chemistry of hydrazones, which are tautomers of azines. (ii)
these compounds can also be synthesised by alternate routes.5 The Azines are highly basic and form salts very easily; in the
azines obtained from the condensation of aldehydes with hydrazine protonated state azines and hydrazones become equivalent.
are called as aldazines whereas the condensation products of Many azines were considered as hydrazones, the distinction
ketones with hydrazine are called as ketazines. 6 Azines are further between azines and hydrazones was rarely highlighted. For
classified as symmetrical azines 1 and unsymmetrical azines 2 (Figure example, the prominent drug belonging to azine class is
1). The azine 3 represents the example of symmetrical azine with N- Guanabenz (5)7 which was always considered as a
methylbenzothiazoline moiety attached to the azine framework guanylhydrazone derivative. Figure 2 shows two tautomeric
(C=N–N=C). The azines of such type have gained attention due to forms of Guanabenz (5A and 5B). The azine form 5B is more
their applications in redox chemistry. Structure 4 represents a special stable energetically (refer section 6).8, 9 Upon protonation, both
class of unsymmetrical azines which carry guanidine group.6 Among the tautomers yield the common species (5C) which closely
all the azines, type 4 azines are different with reference to their resembles the hydrazone framework. Hence, the scientific
community working on guanylhydrazones mostly considered
chemical reactivity. They are 1,1-diamino derivatives of azines (1,1-
1,1-diaminoazines as hydrazones rather than azines.8,9 This
diamino-2,3-diazabutadienes) and hence are highly basic, they
enticing representation lead to a decreased recognition of the
capture proton very easily and form salts.6
importance of azine class of compounds in chemistry.
Department of Medicinal Chemistry, National Institute of Pharmaceutical

Education and Research (NIPER), S.A.S. Nagar, Punjab – 160 062, India.
E-mail: pvbharatam@niper.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 1

ARTICLE Journal Name
hydrazine with two moles of aldehydes/ketones under reflux

condition. A few more examples of conventional methods of
synthesis are given in the next section.
2.1. Conventional synthesis
A very simple route to generate azines involves the
nucleophilic attack of hydrazine (NH 2NH2.H2O) on heterocyclic
quaternary salts13 possessing a good leaving group such as OR,
SR or halogen at position two of thiazole/benzothiazole. Guerin
et al.14 in 2002 reported two strategies (Scheme 1) for the
synthesis of azine 7 which includes (i) the direct refluxing half
equivalent of hydrazine with thiazolium salt or (ii) in a two-step
Figure 2. Guanabenz in its two tautomeric representations and in the protonated
form. procedure by first preparing an intermediate (hydrazino
derivative) in the presence of an excess of hydrazine from the
In the related species semicarbazones and reaction of thiazolium salt 6. Moreover, the authors also
thiosemicarbazones, the hydrazone tautomers are more stable than reported the synthesis of unsymmetrical azine 8 by treating the
azine tautomers.8 This particular fact is also responsible for intermediate with a dithiolium salt. The azine 9 was also
recognizing most of the azines as hydrazones.8 The synthesis of prepared from dithiolium salt by treating with hydrazine
azines can be easily carried out from hydrazine, this factor also led to hydrate.14
the labelling of azines as hydrazones. Hence, all the above listed
factors collectively, justifiably, led to the decreased importance given
to azine class of compounds in the chemical literature. In this review,
all the compounds which prefer to exist in the azine tautomeric state
(based on energy) in their neutral form are included in the discussion.
The literature survey reveals that there are only three
reviews available on azines which covers the literature published up
to 2014. The article by Safari and Gandomi-Ravandi1 included the
synthesis, reactions and coordination complexes of azines. The
review by Wagner-Jauregg includes the reactions originating from
azines and imines.10 Recently, Upadyaya et al. reviewed the
applications of azines as liquid crystals.11 Apart from this, Frenking
and co-workers reviewed some aspects of the bonding situation Scheme 1. The synthetic procedure of the generation of azines 7-9.14
between the main group elements and electron donating ligands. As
a part of this review,12 they discussed some examples of azines which
2.2. Base catalysed synthesis
were studied theoretically and experimentally to understand the
The decomposition of tosylhydrazones gives byproducts
electronic structure details.
such as N-substituted hydrazones or dialkylidenehydrazines
In the current article, we discuss a few interesting topics of
(azines) which are useful intermediates and have wide
azines which were not covered explicitly in the previous reviews.
applications. This information prompted researchers to carry
These topics include structure, electronic structure,
out base promoted decomposition of N-tosylhydrazones for the
isomerism/tautomerism, bonding situation, medicinal chemistry and
synthesis of azines. In 2013, Sha and Wei, 15 reported the
material science. Many developments in the synthesis of
transformation of N-tosylhydrazone 10 to symmetrical azines
heterocycles from azines became available in the recent past, they
11, promoted by a base (NaOH) and solvent (CH3NO2) controlled
are also discussed in this review article. A few novel procedures
metal free method (Scheme 2a). The major challenge which was
of synthesis of azines which were not covered in the previous
overcome by this method is to control the formation of side
reviews are also included in this review article.
products such as oximes or N-substituted hydrazones.15 The
modification in this method has been reported by Luo et al.16
2. Recent developments on the synthesis of for the synthesis of functionalized azines from the
azines decomposition of N-tosylhydrazone 10 (Scheme 2b). The
Because of an increasing interest in substituted azines, authors stated that this method is more environmentally benign
many synthetic procedures have been developed for such as it allows the use of a relatively milder base (Cs 2CO3) instead
compounds. Several methods (~30) are included in the previous of the strong base (NaOH). The reported method offers various
review,1 in the current review, only the most important advantages such as a) broad substrate scope b) no addition of
methods are repeated, but all the latest methods which were additives c) use of a weaker base and d) use of readily available
not included in the earlier review are presented. The examples reactants.16
included in this section are classified in terms of the method
adopted in the synthesis. The conventional method for the
synthesis of azines of 1 and 2 involves the condensation of
2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Journal Nam ARTICLE
Zhang et al.22 reported that the tBuLi promoted direct

intermolecular nucleophilic addition of carbene precursor (18)
to diazo compounds (as N-terminal electrophiles) will lead to
the formation of azines (19, Scheme 5b). The reaction gives high
to excellent yield.
Scheme 2. Base catalysed synthesis of azines from N-tosylhydrazones.15, 16
2.3. Using a method employing in situ

generated carbenes
Several methods involving the participation of carbene
intermediates in the generation of azines have been reported. 17,
18 Azines are often the major products of thermal Scheme 5. Synthesis of azines from in situ carbenes and diazo species.21, 22
decomposition of diazo compounds 12. In 1985, Regitz et al.19
reported the formation of azine (13) by the thermolysis or Recently, an efficient method for the synthesis of azines
photolysis of diazo compounds (Scheme 3).19 The process is (21) has been reported from the reaction of N-heterocyclic
bimolecular, which involves the nucleophilic attack of the carbene (NHC) precursors 20 with N-tosylhydrazones (Scheme
carbon atom of the first diazo compound (which gives carbene 6).23 The authors claim this method to be simple and avoid
by dissociation of N2) on the terminal nitrogen of the second direct use of diazo compounds which often suffer from stability
compound. This may be considered as a thermal and safety concerns. The possible mechanism for the formation
rearrangement. of azines from NHC precursors and N-tosylhydrazones is
depicted in Scheme 6. Under the strongly basic conditions, the
N-tosylhydrazone will convert into diazo compound with the
resonating forms (I and II). Then the pyridoannulated triazole-
based carbene (generated by the deprotonation) will undergo a
nucleophilic addition with the intermediate which gives III (a
Scheme 3. Synthesis of azines by reaction of carbene with diazo compound.19 resonance form of azine). 23
Akiba et al.20 in 1976, reported the synthesis of azine

(15) by the reduction of 3-substituted 2-nitrosoimino-2,3-
dihydrobenzothiazole (14) with lithium aluminium hydride. The
formation of the azines can be described by the formation of an
intermediate i.e. diazo compound which is generated by the
hydride attack on the nitrogen atom of the nitroso group and
carbene (Scheme 4).20
Scheme 6. Synthesis of azines reported by Wei et al.23
Scheme 4. Formation of azines by reduction of 3-substituted 2-nitrosoimino-2,3- 2.4. Metal catalysed synthesis
dihydrobenzothiazole.20
Zhao et al.24 reported the formation of symmetrical
In 2016, Guo et al.21
developed a facile and efficient azines (23) which were produced by the copper catalyzed
method for the synthesis of structurally diverse azines (17) by homocoupling of oximes 22 (Scheme 7). The advantages
the reaction of the electrophilic reaction of 2,2,2- associated with this methodology include high functional group
trifluorodiazoethane (CF3CHN2) with the in situ generated N- tolerance, use of easily available oximes, good to excellent
heterocyclic carbenes from salt 16 under the basic conditions yields and mild reaction conditions. Another major advantage
(Scheme 5a). The authors suggested the notable features of of this method is to avoid the use of hazardous hydrazine
reaction are operational simplicity, mild reaction conditions, hydrate.
and easily accessible starting material.

Scheme 7. Copper catalysed homocoupling of oximes to generate azines.24
Bauer et al.5 in 2016 reported the synthesis of

symmetrical azines (24) from the reaction of alcohols and
hydrazine hydrate using a ruthenium pincer complex (Scheme
8). This method led to good conversion and yields for the
dehydrogenative coupling of benzylic as well as aliphatic
alcohols. Authors established that this one-step strategy
possesses the following advantages a) atom economical, b)
environmentally benign, c) use of readily available starting
material. The mechanistic investigation suggested that under
the reaction conditions, the formation of an active
dearomatized catalyst (complex 2) from complex 1 occurs with
the assistance of excess hydrazine prior to the actual catalytic
cycle.5
Scheme 9. Nickel(II) catalysed synthesis of azine.25
Inspired from the direct transformation of alcohol into

azines by the use of less costly metal complex (Ni complex)
Scheme 8. Synthesis of azine by dehydrogenative coupling of alcohols and recently Sheikh et al.26 reported the dehydrogenative coupling
hydrazine hydrate catalysed by ruthenium pincer complex.5
of alcohols with hydrazine hydrate to obtain symmetrical
A controlled tandem synthetic procedure has been azines. The reaction is catalysed by the use of earth abundant
adopted by Chakraborty et al. 25 for the synthesis of azines (24) and less costly Ni-based NNN-pincer transition metal complex
by the treatment of various alcohols and hydrazine hydrate in i.e. Ni(BPEA)(Cl)2. The authors carried out the quantum
the presence of Ni(II) complex of 2,6-bis(phenylazo)pyridine as chemical calculations to understand the mechanism of azine
a catalyst (Scheme 9). This report represents the first example formation.26
of ligand redox-controlled synthesis of azines and the marked Martin-Gago and coworkers adopted “on-surface”
advantages of this reaction are a) the use of earth abundant approach to generate quinoneazine from the coupling of para-
metal catalyst, b) milder reaction conditions, c) aerobic aminophenol 25.27 The authors described the mechanism of
condition and d) wide substrate scope. The reaction proceeds formation of azines using a combination of theoretical and
via the formation of an aza-anion radical intermediate (Scheme experimental methods. Owing to a strong surface-molecule
9) which was confirmed by EPR spectrum taken after the interaction between the synthesised azine and Cu(110) surface,
reaction between catalyst 1 and hydrazine hydrate in the quinoneazine molecule accommodates 1.2 electrons at its
benzylalcohol at room temperature. Interestingly, this synthetic carbonyl ends which induces the redistribution of
route has been utilized for the synthesis of phthalazine (a cyclic intramolecular charge and thus leads to the partial conjugation
azine) from 1,2-benzenedimethanol and hydrazine hydrate via of the rings as well as azo-character at the nitrogen sites (26,
intramolecular coupling in a single step.25 Scheme 10).27
Scheme 10. Synthesis of quinoneazine by Cu(110) using on-surface approach.27

Journal Nam ARTICLE

Scheme 13. Synthesis of azine derivatives by the reaction of carbonyl compounds
The synthesis of 9-Fluorenone azine (27) was described with solid hydrazine (NH3+NHCO2-).30, 31
recently from the reaction of 9-Fluorenone hydrazone with
FeCl3 in chloroform as a solvent (Scheme 11). The proposed Arun and Sankaran32 synthesised the conjugated azines
mechanism involves the activation of iminic carbon by the (31) in the presence of acid catalyst sulphated-titania (TiO2-
coordination with FeCl3. This activated imino-carbon atom of SO42-) from fluorenone hydrazone with substituted aldehydes
hydrazone is then attacked by nucleophilic amino group of or acetophenones (Scheme 14). The important features of the
another hydrazone to form symmetrical azine and asymmetrical reaction are (i) it can be carried out in solvent free condition,
azines with the elimination of FeCl3 and hydrazine moiety.28 and (ii) it involves simple operating procedure, (iii) short
reaction times and (iv) catalyst is recyclable.
Scheme 11. FeCl3 catalysed synthesis of 9-Fluorenone azine.28

Scheme 14. Acid catalysed solid state synthesis of fluorenone based azines.32
2.5. Iodine catalydsed synthesis
In 2007, Nanjundaswamy and Pasha29 reported the iodine 2.7. Microwave assisted methods
catalysed synthesis of symmetrical azine by the treatment of A fast, efficient and environmentally benign solvent-free
NH2NH2.H2O with carbonyl compounds at 0–10°C. This method one pot synthesis of azines was developed by Simeonov et al.33
affords the rapid generation of symmetrical azines (28) in excellent by the treatment of aldehyde with semicarbazide hydrochloride
yields in 1 to 4 min (Scheme 12). In case of liquid carbonyls, the or t-butyl carbazate under microwave irradiation. The reaction
reactions have been carried out without solvent whereas in case of proceeds via the formation of semicarbazone or carbazate
solid substrates minimum amount of either THF or methanol can be intermediates, which will transform into azine (32, Scheme
used to dissolve the substrate. 15a). The main advantage of this approach in comparison to the
conventional heating is energy saving and avoiding the use of
toxic hydrazine. Aly et al.34 reported the one-pot synthesis of
azines from thiosemicarbazones. Authors described that
thermolysis and/or microwave irradiation of
thiosemicarbazones resulted in the formation of the
Scheme 12. Iodine catalysed synthesis of azines.29 corresponding isothiocyanates, which upon addition of either
activated nitriles or aldehydes furnished various types of azines
2.6. Solvent free synthesis/ Solid state (33, Scheme 15b).
synthesis
Solid hydrazine (carbonate salt of hydrazine, which can
be synthesised by the reaction of aqueous hydrazine with
supercritical CO2) is as reactive as liquid hydrazine even in the
absence of solvents. In 2011, Lee et al.30 synthesised the azine
(29) from the reaction of solid hydrazine (NH3+NHCO2-) with
aldehyde/ketone (Scheme 13a). They also reported the synthesis
of azines (30) by grinding solid hydrazine (NH3+NHCO2-) with
carbonyl and dicarbonyl compounds; neither catalyst nor any
additive is required for performing the reaction. This method is Scheme 15. Microwave assisted synthesis of azines.
easy to perform, environmentally safe, and readily scalable
(Scheme 13b).31 2.8. By electrochemical oxidation
The azines were also synthesised by electrochemical
oxidation of ketone allylhydrazones (34) in the presence of
sodium methoxide and potassium iodide (Scheme 16).35 The
electro-oxidation leads to the formation of C-N double bond
between an allylic carbon atom and the nitrogen atom of the
hydrazone to afford a conjugated system (35). The best yields
were obtained when sodium methoxide (0.5 equiv.) and a
catalytic amount of potassium iodide were used as the
supporting electrolytes at room temperature. The authors

suggested that this electro-oxidation reaction is 2e- oxidation 3. Crystal structures of azines
process where KI acts as the source of iodide ions.
Azines contain two azomethine groups (C=N) which are
linked by a nitrogen-nitrogen single bond (N-N) and hence
structural preferences across the two double bonds in azines
are expected to be similar to that in 1,3-butadienes. The
conformation across 1,3-butadiene can be considered in two
ways, one is s-transoidal conformation and the other is s-
Scheme 16. Synthesis of azine by electrochemical oxidation.35 cisoidal gauche conformation.40 Similarly, in azines also two
conformations can be expected, i.e. s-transoidal and s-cisoidal
2.9. Miscellaneous methods gauche. In addition, across each of the C=N double bonds, E/Z
isomerisation can be expected. The crystal structure details of
Chen et al.36 reported a highly efficient and practical
selected 17 azines are provided in Table 1 (see Table SI-1 for a
protocol for the synthesis of azine 36, which involves the
comprehensive list of crystal structures of azines).
coupling of 3-ethyl-2-benzothiazolinone hydrazone (37) with 3-
The crystal structure data of various azines obtained
ethyl-2-iminobenzothiazoline bromide salt (38) using pyridine
from Cambridge Crystallographic Data Centre (CCDC) showed
as both solvent as well as base under refluxing condition for 12
that C-N-N-C torsional angle is between 110-180°.23, 41-96 It is
h (Scheme 17a).36 Sumran et al.37 reported the serendipitous,
interesting to note that s-trans conformation (C-N-N-C- dihedral
formation of azine 39 from the reaction of 3-hydrazonobutan-
angle ~180°) of azine is present in less than 50% of the crystal
2-one oxime (40) with aromatic aldehydes (Scheme 17b). The
structures reported and in the remaining cases, azines exhibit
CF3-substituted azines (41) have been synthesised by aza-Wittig
transoidal gauche conformation. The torsional angle data
reaction of aldehydes with trifluorodiazoethane. 38 The reaction
shown in Table 1 clearly establishes that s-transoidal gauche
proceeds via phosphazene intermediate P1, which would be
conformation is the preferred structure in most of the azines.
generated by the reaction of CF3CHN2 to PPh3. Further, the aza-
No structure with s-cisoidal gauche was noticed. The torsional
Wittig process of P1 with aldehydes gives azines (41) (Scheme
angle parameter was used to evaluate the extent/lack of
17c). The synthesis of symmetrical azines (42) was achieved
conjugation in azines, whereas, bond length parameters can be
with excellent yield by the treatment of acetonitrile-
used to understand the chemical bonding between the C=N and
H2O2/(NH4)2CO3 with aldehydes (Scheme 17d).39 This method
N–N bond in azines.
possesses the advantage of not using hydrazine. The authors
Most of the crystal structure analysis was carried out to
reported that the reaction will not proceed in the absence of
understand the stereochemistry and stereoelectronics of the
acetonitrile, as acetonitrile plays a very important role by
azines as they were found to be potential candidates for the
reacting with H2O2 under pH controlled condition to generate
nonlinear optic (NLO) materials. A few observations can be
peroxycarboximidic acid intermediate. The generated
made from the crystal structure data of azines as discussed
intermediate reacts rapidly with aldehyde in the presence of
below. In 3-Acetyl-4-(2-chlorophenyl)-4-hydroxy-2-
ammonium carbonate to produce azines.
methoxycrotonic acid lactone 43 (Entries 3 and 4, Table 1) two
conformers were noticed.42 Kurihara and co-workers42 reported
stereo chemical differences for two conformational isomers;
significant differences in the two isomers are due to deviation
across C-N-N-C torsional angle. The structure with 180°
torsional angle is red in colour and the structure with 114°
torsional angle is yellow in colour. In the crystal structure of the
opioid analgesic agent naltrexonazine 44 (entry 5, Table 1), the
deviation from s-trans arrangement is very significant
(118.6o).43 Similarly, the benzoxazepine 45 containing species
(entry 6, Table 1) shows strong deviation in torsional angle
(124.58o).45 Glaser and co-worker evaluated the stereo and
electronic character of acetophenone azine.48, 50, 53, 55 The halo
substituted systems showed strong deviation from s-trans
arrangement, for example, the diiodo system 46 (entry 7, Table
1) showed a torsional angle of 141.8°. The authors expected a
torsional angle value < 124° (but found 141.8o), this
phenomenon was attributed to the crystal packing factors. For
the dinitro compound 47 two conformers (entries 8 and 9, Table
Scheme 17. Miscellaneous methods of generating azine.
1) were reported, the differences in the two structures are
mostly due to torsional angle - the red isomer (~155°) and the
white isomer (~113°).

Table 1. The reported crystal structures of a few azines along with some important geometrical features.a
Torsional angle Bond Length (Å)
Entry Structure CCDC No. Year Purpose
-C=N-N=C- (°) -C=N- =N-N=
1.268,
1. 1866599 2019 Polymorphism 179.76
1.323
1.392
1.273,
2. 1866600 2019 Polymorphism 173.01
1.332
1.389
3. 1100004 1983 Isomerism 180.00 1.290 1.380
4. 1253603 1983 Isomerism 114.74 1.282 1.381
5. 1158099 1987 Opioid ligand 118.60 1.27 3 1.412
As a substrate for the

6. 1257113 1990 synthesis of 124.58 1.309, 1.283 1.390
benzoxazepine
Stereoelectronic,
139916 stereochemistry,
7. 1999 141.82 1.288 1.39.6
crystal packing for
NLO property
Crystal structure
8. 984383 2018 155.22 1.281, 1.279 1.375
determination
Crystal structure
9. 984384 2018 113.37 1.286, 1.288 1.390
determination
Push Pull donor

10. 236036 2004 175.97 1.332, 1.370 1.319
acceptor azine

Synthesis and crystal

11. 1202608 2012 179.00 1.323, 1.315 1.362
structure
12. 1473843 2016 Tautomerism 179.74 1.327, 1.278 1.385
13. 1473844 2016 Tautomerism in azine 161.86 1.300, 1.330 1.386
To study the
coordination mode of
14. 770436 2011 180.00 1.300 1.412
azines (Chances for
catalysis)
To study the
coordination mode of
15. 770437 2011 180.00 1.295 1.410
azines (Chances for
catalysis)
158.17
Coordination
16. 1183096 1989 chemistry of azine 1.282, 1.260 1.410
with metal (palladium)
Charge transfer
1.322,
17. 695874 2009 complex and radical 180.00 1.354
1.312
cation of azine
Charge transfer
18. 695875 2009 complex and radical 180.00 1.286 1.410
cation of azine
Synthesis of azine
19. 1520662 2017 179.33 1.320, 1.278 1.372
from NHC precursor
aRefer Table SI-1 for an expanded list of crystal structures of azines.

In general, in azines, the average C-N double bond length suggested that although the C=N–N=C spacer consist of two
is of the order of 1.28 Å, the average N-N bond length is of the imine groups joined by N-N single bond and thus qualify to have
order of 1.40 Å, these values can be considered as standard conjugation but as per the results of solid state study where the
values. But in certain cases significant deviation from the twist in conformation across C=N-N=C has noted it is
standard values was noticed. For example, Choytun et al. appropriate to consider “conjugation stopper” property of this
reported fluorenone based azine 48 (entry 10, Table 1) in which group.
two different C-N bond lengths 1.33 Å and 1.37 Å are reported The “conjugation stopper” concept was also supported by
which are much longer than the average values. 61 In the same several previously reported electrochemical studies. 50 Lund in
molecule the N-N bond length was reported to be very short 1959 carried out electrochemical studies on benzaldehyde azine
1.319 Å. This is quite surprising because such short bond lengths and of the benzylhydrazone of benzaldehyde. They carried out
are found in diazo compounds, the authors attributed this the reduction and found no change in the reduction potential of
phenomenon to the push-pull factors.61 Similarly, Davydov et al. azine and hydrazone suggesting the lack of conjugation in
reported the crystal structure of dihydroisoquinolineylidin azine azine.100 Ludvik et al.101 in 1998 carried out electrochemical
49 in which the C-N bond length values are 1.32, Å and 1.31 Å reduction of metamitron (a synthetic compound with triazinone
whereas the N-N bond length is 1.36 Å (entry 11, Table 1).85 moiety, used as a herbicide that contains an azine group as a
Similarly, the work by Lasri et al. reported fluorenone part of triazine ring). The authors reported the electrochemical
containing system 27 (Scheme 11) with highly deviated reduction of metamitron in 2-e- steps.101 In 2000, Zuman and
geometrical parameters.91 The crystal structure of diaminoazine Ludvik carried out studies on a series of triazines and acyclic
compound 50, 51 (Entries 12 and 13, Table 1) reported by our azines. From their studies they concluded that conjugation is
group showed that the C-N bond length involving C(NH2)2 unit is minimal or absent in both cyclic and acyclic azines. 102 Sauro and
longer (1.327 and 1.330 Å) than the standard value 1.28 Å.9 In Workentin104 carried out electrochemical studies in solution
the drug molecule Guanabenz 5 E/Z isomers were observed state to see whether the lack of conjugation observed in the
(Entry 1 and 2, Table 1).97 A comparison between the crystal solid state is also observable in solution state as the molecules
structures of entries 14 and 15 revealed that there are no have much more conformational freedom in the solution state.
structural differences between acyclic 52 (Entry 14) and cyclic They carried out a systematic study to examine the
azines 53 (Entry 15). Many structures with metal coordination electrochemical properties of a series of related azines and
of azines are reported in which the geometrical parameters observed the change in the reduction potential upon change in
were not significantly modified upon coordination with substituent on the azine bridge. Hence, it was suggested that
transition metals 54 (e.g. entry 16, Table 1).81, 89 Comparison conjugation in azine is present in solution state, but to a lower
between the two crystal structures of selenium compounds extent.103 Authors also studied the reduction potential of the
55_PF6, 55_TCNQ (entries 17 and 18, Table 1) indicates that the corresponding azine radical anions and found greater impact of
electronic distribution within the molecule is quite disturbed substituents on the reduction potential. The absorption
from the salt form to the neutral form. In the salt of PF 6-, the N- spectroscopy and qualitative semi-empirical calculations on the
N bond length is 1.354 Å but in the charged transfer complex radical anion of azines indicated stronger conjugative
with TCNQ, the N-N bond length is 1.410 Å.73 Wei et al. reported interaction103 suggesting the presence of strong conjugation in
azines containing trizolopyridine ring 56 (as an N-heterocyclic the radical anion of azines.
carbene) in which the C-N and N-N bond lengths are significantly Nakano et al.65 in 2006, reported the crystal structure of
deviated (entry 19, Table 1) from standard values.23 (1Z,2Z)-1,2-Bis(3-methyl-2,3-dihydro-1,3-benzothiazol-2-
Apart from the above observed geometrical factors a lot ylidene)hydrazine (3). The molecular geometry of this azine
of physical organic chemistry issues were considered using the including C=N–N=C is completely planar. The geometry across
structural information provided in Table 1 and Table S1. These both C=N double bonds are Z,Z configuration with C1–N1–N2
are related to conjugation, E/Z isomerisation, tautomerism and and N1–N2–C9 angles of 111.0° and 110.2° respectively (refer
polymorphism as well as chemical bonding, the details are Table S1). The N1–N2 and C1–N1 (C2-N2) bond distances are
provided in the following sections. 1.409 Å and 1.286 Å (1.294 Å), respectively indicating C-N single
4. Conjugation in azines bond and C=N double bond. These geometrical data are
comparable to those of formaldehyde azine, where the N–N
Based on their relationship to butadiene, it is expected that
and C=N bond lengths are 1.418 Å and 1.277 Å, respectively, and
electronic delocalisation would occur in azines similar to that in
H-C-N and C–N–N bond angles are 120.7° and 111.4°
butadienes, and the two expected resonance structures are I
respectively. From the analysis of the crystal structure of azine
and II (Figure 3A). Glaser et al. examined the possible resonance
3, Nakano et al. concluded that “These bond distances (C=N and
structures of the symmetric and asymmetric acetophenone
N–N) suggest less delocalisation of π electrons, but since the
azines,98 and noticed the absence of conjugation in azines. This
molecule is completely flat and thus π-conjugation is possible
argument was further supported by NMR spectroscopic studies
between C=N groups”.
carried out on various azines where no change in the chemical
Choytun et al.61 in 2004 studied the extent of
shifts value of the aromatic proton of the donor ring was
conjugation/delocalisation in several azines (27, 28b 57-62)
observed by the nature of the substituent on the acceptor ring.
with push-pull donor acceptor substituents (Figure 3B, Table S1)
The same observation was noted for the 13C chemical shift value
since such systems are attractive NLO material. Azines under
of the donor ring.99 From all these studies, Glaser et al.
study were mainly prepared by the combination of an NHC with

a diazoalkane. All compounds were characterized

spectroscopically and by X–ray crystallography.
The extent of delocalisation within azines is generally
evaluated using the geometrical parameters such as C–N, and
N–N bond lengths and compared with 28b. The analysis of
crystal structure data clearly suggests that azine 48 has
significantly shorter N–N bond length (1.32 Ǻ) and
correspondingly longer C–N bond lengths than those found in
azines similar to 28b (Table S1). From this study, it was
concluded that the geometrical parameters are suggesting the
presence of delocalisation in azines 57-62 and hence represent
a push-pull system which can be exploited for their application
as nonlinear optics.
McLoughlin et al. in 2007, carried out quantum chemical
studies on acetophenone azines to evaluate their conjugation
property.104 Authors carried out a series of calculations at the
B3LYP/6-31G(d) level for 2,3-diaza-1,3-butadienes (63-67) and
1,3-butadienes (63D–67D, Figure 4) and from the results of
these calculations they argued that that azine linkage supports
conjugation not only between the C=N double bonds but also
between double bonds and lone pairs of nitrogen atoms. Hence,
the authors suggested that it is more appropriate to refer to
azines as “conjugation switches” rather than conjugation
stoppers. Such property of azines found its application as
nonlinear optics105 and liquid crystals.106, 107 The “conjugation
switch” property suggested by McLoughlin et al. is also present
in azines where the terminal carbon of the azine framework
(C=N–N=C) is part of a carbocyclic/heterocyclic ring, hence this
class of azines are probably different and exhibit conjugation
across the azine framework, unlike examples of azines
(acetophenone azines) studied by Glaser and his group which
exhibit “conjugation stopper” property. Further, clarity Figure 3. Push-pull azines (A) and their mesomeric representation (B).
Commented [B1]: Rearrange 3A, 3B
regarding the conjugation across the C–N–N–C- framework is
warranted.

Journal Nam ARTICLE
Figure 5. Benzophenone-9-anthraldehyde azine (68), benzophenone-9-acridine-

aldehyde azine (69) and 9-anthraldehydc azine (70) in their E isomeric forms.
Figure 6. Stereoselective formation of E,Z azine by the dimerisation of diazo

compounds and its thermal isomerisation to E,E isomer.
Recently, we explored the structural properties of

diaminoazines and studied the mechanism of E/Z isomerisation
in these azines using DFT methods (Scheme 18). These azines
Figure 4. Conjugation switches azines (63-67) and corresponding dienes (63D-67D).
owing to the presence of C=N groups can undergo E/Z
isomerism. The E/Z isomerism can be possible by three
5. Isomerism in azines mechanisms namely, (i) rotation, (ii) inversion and (iii) mixed
The structural diversity present in the azines suggests rotation and inversion. The DFT study on azine (51) was carried
that they can exhibit isomerism. Azines can exhibit mainly three out to investigate the mechanism associated with the thermal
types of isomerism, (i) geometrical isomerism, due to the isomerism and the study suggested that the percentage of
presence of C=N imine bond, and (ii) conformational isomerism, inversion mechanism and rotation mechanism involved for E/Z
due to the rotation across N-N single bond. A few examples isomerism in these azines is 50:50 and hence these azines can
were highlighted in section 3, further details are presented in undergo E/Z isomerism by both rotation and N inversion. The
this section. calculated barrier for N-inversion at N2 is 22.7 kcal/mol and
38.7 kcal/mol at N3 nitrogen.9 Similarly, E/Z isomerism was
5.1 Geometrical isomerism in azines noticed in the drug Guanabenz 5 (free base).97
Aldazines and ketazines are the azines derived from the
condensation reaction of the aldehyde/ketone with hydrazine.
These azines have a tendency to form E/Z isomers due to
geometrical choice across C=N bonds. Appenroth et al.108-110 in
1981 studied photochemical and thermal E/Z isomerisation of
the benzophenone-9-anthraldazine (68), benzophenone-9-
acridine-aldehyde azine (69) and 9-anthraldehydic azine (70)
(Figure 5).108 Extensive studies including quantum chemical Scheme 18. Proposed Mechanism of E/Z isomerism across C=N in diaminoazine
analysis were reported on the photochemical E/Z using DFT study. In this azine, E/Z isomerism is also possible across C=C, since this
aspect have been already discussed in many reports, not discussed in this
isomersisation of azines, following this work. Further, it was example.
observed that the photochromism is also associated with

thermochromism in these systems. 111 Kolb and Hua in 1984, reported the possible geometrical
Abelt and Pleir in 1989 examined the reaction of isomers in three compounds naloxone-estrone azine,
phenyldiazomethane and 1-diazo-1-phenylethane to form naltrexonazine (44, Figure 7) and oxymorphonazine.112 The
isomers of azines (28a and 28b).17 The reaction is claimed to be possibility of anti-anti (E,E) anti-syn (E,Z) and syn-syn (Z,Z)
stereoselective for the E,Z isomer formation in the ratio (>95:5 isomers in naltrexonazine and oxymorphonazine synthesised
E,Z:E,E, Figure 6). The thermal isomerisation of E,Z isomer of from corresponding hydrazones (a mixture of 80% of anti and
azine 28a and 28b to their alternative geometrical E,E isomers 20% of syn) was suggested and analysed by 1H and 13C NMR
was studied by temperature dependent NMR in DMSO-d6 analysis. The synthesised azines indicate the presence of
solution. The experimentally calculated barrier for isomerism multiple peaks which could be due to the presence of many
was found to be 22.4 kcal/mol, this value is comparable to the isomers in the reaction mixture. Based on the NMR analysis, the
barrier reported by Appenroth et al.111 anti-anti isomer was assigned as the major product in both

cases. On the other hand in case of naloxonazine-estrone azine, degradation study was carried out which suggests that isomer II
configurationally pure anti-anti isomer was observed as it was degrades in the range of 463-483 K whereas isomer I degrades
synthesised from pure anti-estrone hydrazone.112 in the range of 435-483 K. Computational analysis using Semi-
Lipkowska et al.43 carried out the synthesis and X-Ray empirical CNDO/2 method indicated that the twisted isomer is
crystallographic studies to understand the configuration and energetically more stable by ~15 kJ/mol. This conformational
conformation of naltrexonazine. Under acid conditions, from isomerism indicates that the C=N-N=C conjugation is very weak.
hydrazine hydrochloride and naltrexone hydrochloride in
refluxing methanol they isolated only one isomer in 93% yield
(labelled it as anti-anti isomer, Figure 7). The crystal structure
of this isomer could be obtained by recrystallisation in isopropyl
alcohol. As discussed in section 3, this compound exhibits s-
transoidal gauche conformation (118o) across the C=N-N=C
framework. The authors also reported the generation of
another isomer in neutral medium when the compound was
synthesised using naltrexone (free base) with anhydrous
hydrazine in methanol, which was recognized on the basis of
NMR (labelled syn-anti isomer). Upon heating (with time), the Figure 8. The two conformers of azine of 3-Acetyl-4-(2-chlorophenyl)-4-hydroxy-
2- methoxycrotonic acid lactone (43) observed in the solid state.
authors reported the conversion of the second isomer to the
major isomer.43 The conformational isomerism observed by Tighadouini
et al. 113 in 4-nitroacetophenonazine (47 entries 8 and 9, Table
1) also deserves elaborate discussion. The reaction between
hydrazine hydrate and p-nitroacetophenone yields the red
crystalline species, which upon thermal treatment in methanol
undergoes thermal isomerisation to produce the white
crystalline solid. The coloured species was with C=N-N=C
torsional angle 155o is close to being s-trans isomer and the
white species with 113o torsional angle can be considered as the
Figure 7. The crystal structure of anti-anti isomer of naltrexonazine (44), showing
the quite twisted conformation across the C=N-N=C central unit.43 s-transoidal gauche conformer. The 3D structures of these two
conformers are shown in Figure 9 (CCDC-Mercury). The
5.2 Conformational isomerism in azines interconversion rate between the two conformers is 85:15
Conformational isomers are possible in azines by (red:white) under methanol refluxing condition. The authors
rotation across N–N single bond. The conformation of aromatic suggested that the red isomer is semi-flexible due to the
azines is controlled by a chain of four atoms: C=N–N=C. When presence of conjugation.
the two groups are arranged anti to each other across -N–N-
plane with C=N–N=C dihedral angle of 180°, the azines exhibit
s-trans conformation and when the two groups are arranged on
the same side of -N–N- plane with C=N–N=C dihedral angle of 0°
then the azines exhibit s-cis conformation. When the two
groups are arranged anti to each other across -N–N- plane with
C=N–N=C dihedral angle of 180°, the azines exhibit s-trans
conformation and when the two groups are arranged on the
same side of -N–N- plane with C=N–N=C dihedral angle of 0°
then the azines exhibit s-cis conformation. Many crystal
structures of azines have been reported (Table 1) to understand
the stereochemistry and stereoelectronics. From these studies
Figure 9. Conformational isomers of (1E,2E)-bis[1-(4-nitrophenyl)ethylidene]
it may be concluded that all the conjugation stopper azines exist hydrazine observed in single crystal XRD.
in s-transoidal gauche conformation with torsional angle across
C=N–N=C is in the range of 115-165° whereas other azines exist The matrix isolation infrared spectroscopic study and
in s-trans conformation with the torsional angle across C=N-N=C quantum chemical calculations have been carried out on 2'-
is ~180°, in such azines the conjugation was found to be hydroxyacetophenone azine (71, Figure 10) by Grzegorzek et
maximal (Table 1). al.114 Density functional Theory (DFT) B3LYP/6-311++G(2d,2p)
As pointed out in section 3, Ishida et al.42 observed the calculations suggested the presence of two conformers for the
conformational isomers of 3-Acetyl-4-(2-chlorophenyl)-4- lowest energy E/E configuration of 2'-hydroxyacetophenone
hydroxy-2-methoxycrotonic acid lactone (43, Table 1, entry 3 azine. The conformers differ in the value of a C=N-N=C dihedral
and 4); Figure 8 shows the 3D structures of the two isomers angle – 180° for a planar s-trans conformer and 155° for a non-
(generated from the CCDC-Mercury software). The thermal planar conformer.

Journal Nam ARTICLE
The authors also studied the 10-(2-Benzothiazolylazo)-9-

Phenanthrol which is analogue to azine 49 where the
dihydroisoquinoline fragment is replaced with 2-benzothiazolyl
fragment (Scheme 20).115 In this case also three tautomers i.e.
azine (72), hydrazone (73A) and azo (73B) can be expected.
Figure 10. Conformational isomerism in 2'-hydroxyacetophenone azine (71).
The quantum chemical calculations suggested that the energy

difference between the conformers very small (0.09 kJ/mol).
The optimized 3D geometries of both the conformers suggested
the presence of intramolecular OH‧‧‧N hydrogen bonds which
get weaken when planar conformer becomes non-planar. The
calculated barrier for conformational interconversion is very Scheme 20. Tautomeic equilibria in 10-(2-Benzothiazolylazo)-9-Phenanthrol.
low, ~1 kJ/mol.114 The authors recorded the FTIR spectra of the
two isomers of hydroxyacetophenone azine under matrix The quantum chemical calculations suggest that all the
isolated conditions. The presence of two conformers of azine three isomers are close in energy with the azine tautomer being
was concluded based on (i) the band intensities, (ii) strength of more stable on a relative scale. However, NMR, IR, UV, and X-
O-H‧‧‧N hydrogen bonds. ray diffraction studies indicated that, in the solution and solid
states, the compound prefers to exist in hydrazone form. This
6. Tautomerism in azines hydrazone tautomer is stabilized by the intramolecular N2-H‧‧
Apart from the geometrical isomerism and ‧‧O6 hydrogen bond. The crystal structure also reveals that
conformational isomerism, the prototropic isomerism in azines benzothiazolyl and phenanthrenequinone fragments are nearly
has gained importance. Davydov et al.85 carried out the coplanar.
synthesis of 9(E)-Phenanthrene-9-10[(1Z)-3,3-Dimethyl-3,4- Khouzani et al.116 studied the tautomerism in 2-
Dihydroisoquinoline-1(2H)-ylidene (49) to study its ability to ketomethylquinolineazines in solution state by NMR
form coordination compounds with metal salts, since such spectroscopy. They observed the presence of azine (74B) and
metal complexes are known for their diverse pharmacological hydrazone (74A) tautomers in equilibrium in CDCl3 for most of
activities. The structural features present in this molecule the synthesised compounds. Based on UV, IR and NMR data, it
suggest that the molecule can exhibit hydrazone-azine-azo was reported that in case of three compounds, the equilibrium
tautomeric equilibrium (Scheme 19). shifted towards azine tautomers, whereas in one case exclusive
hydrazone form reported (Scheme 21).116
Scheme 21. Azine-hydrazone tautomerism in 2-ketomethylquinolineazines.
The tautomerism/isomerism in 1-Hydrazinophthalazine

based hydrazone (Scheme 22) was reported by Giorgi et al.117
The 1-Hydrazinophthalazine, commonly known as hydralazine
is an effective drug used for the emergency reduction of blood
pressure in hypertensive crisis. 1-Hydrazinophthalazine based
Scheme 19. Tautomeric equilibria in 9(E)-Phenanthrene-9-10[(1Z)-3,3-Dimethyl- hydrazone was prepared by the reaction between the
3,4-Dihydroisoquinoline-1(2H)-ylidene.
corresponding 1-Hydrazinophthalazine with methyl pyruvate or
pyruvaldehyde in ethanolic or methanolic solutions. Crystal
The X-ray diffraction study suggested that the molecule
structures of two compounds were obtained, one in hydrazone
exists as azine tautomer in the solid state (Table 1, Entry 11), as
form 75A and the other in azine state 75B (Scheme 22). Both
it is evident from the location of “active” hydrogen which is
the structures prefer the E-state in terms of geometrical
located at the N(1) atom of the dihydroisoquinoline fragment.
isomerism.
In the crystal structure, the azine tautomer has cis,trans (Z,E)
configuration which allows the molecule to form intramolecular
hydrogen bond N(1)-H‧‧‧‧N(3), giving rise to five-membered
ring.

tautomer is preferred, whereas in case of amidrazones and

guanylhydrazones, azine tautomer is preferred (Figure 13).
Subsequently, the energy differences between the two isomers
among many biologically relevant molecules was estimated,
which clearly established that all the species prefer the azine
tautomeric state. This energy preference can be attributed to
the gain in conjugation and strong n* second order
Scheme 22. Azine-hydrazone tautomerism in 1-Hydrazinophthalazine based delocalisation.8 It was noticed
hydrazone.
The presence of azine tautomer 75B influences the

supramolecular chemistry of 75, and in particular their crystal
packings (Figure 11). The crystal packing of 75 suggests that the
azine tautomer is stabilized by both van der Waals and
Figure 13. A) Azine-hydrazone tautomerism in guanylhydrazones; B) Two possible
hydrogen bonding interactions. The molecule is involved in tautomers of Guanabenz in their neutral form
intramolecular and intermolecular hydrogen bond interaction
with H‧‧‧‧N-H intermolecular hydrogen bond distance equal that such energy preference is additive as species with two /
to 2.192Å. (Figure 11).117 three azine units in one molecule showed very strong
preference towards azine tautomeric state. Further, the
importance of azine tautomeric state in drug-receptor
interactions was established by performing molecular docking
analysis of Guanabenz 5 in the 3D structure of MAO-A
(Monoamine oxidase A).
Continuing our effort, a series of simple and conjugated
azines were synthesised and their structural analysis was
carried to establish the tautomeric preferences. 9 In all cases,
azine tautomer was noticed in solution state. The crystal
structures of two species 50, 51 were generated which
confirmed the azine preference. Quantum chemical analysis
Figure 11. Crystal structure of 75B showing dimer with intra and intermolecular was carried out to explore the reasons for the tautomeric
hydrogen bond interaction. Hydrogen bonds are shown by doted lines. Bond
distances are in Å. preferences. From this work, it can be confidently concluded
that all the guanylhydrozones reported in the literature need to
The crystal structures of (1Z)-Phthalazin-1(2H)-one be considered as azines rather than hydrazone derivatives.
isopropylidenehydrazone (76, Figure 12) was reported in 2007
where azine tautomer was found to exist in the solid state. 118
7. Polymorphism in azines
The crystal structure analysis revealed that the molecule is
stabilized by C—H ‧ ‧ ‧ ‧ N and N—H ‧ ‧ ‧ ‧ N intermolecular Polymorphism is a solid state property of a molecule in
hydrogen bonds. The N—H ‧ ‧ ‧ ‧ N hydrogen bonds forms which molecule exists in more than one solid form or crystalline
2
centrosymmetric R 2 (6) synthon, while the three C—H ‧‧‧‧N state.119, 120 These morphological changes lead to several
2 2 2
hydrogen bonds forms edge-fused R2(7) R2(7) R2(10) motifs. changes associated with their handling, especially in the field of
pharmaceutical sciences, the polymorphic changes play major
role in the preparation of drug-excipient complexes and
subsequently, the drug release. 121 The morphological
properties of the drugs are directly related to the structural
preferences of the drug molecules, though one-to-one
correspondence is not easy to predict. The structural
preferences of azines appear to have significant impact on the
morphological aspects of the solid material associated with
azines. A few examples of the same are listed below. In this
context, it can be considered that all the structural aspects on
azines discussed in sections 4-6 (above) play a role in
Figure 12: ORTEP diagram of (1Z)-Phthalazin-1(2H)-one isopropylidenehydrazone. polymorphism of the corresponding azines. For example, the
A) Monomer; B) Dimer showing inter and intramolecular hydrogen bonds. conformational differences noticed in –C=N-N-C- lead to
conformational polymorphism in these 3-Acetyl-4-(2-
Our group explored the tautomeric preferences in azines chlorophenyl)-4-hydroxy-2-methoxycrotonic acid lactone
using computational and experimental methods. 8, 9 Initially, we azines 43.42 Similarly, the torsional angle differences in 4-
performed quantum chemical studies which showed that in nitroacetophenonazine95 (47) can be considered to cause
case of semicarbazones and thiosemicarbazones, hydrozone conformational polymorphism. A few more details on

Journal Nam ARTICLE
polymorphism in azines were reported, the same are presented inversion in space groups P21/n for Form Ia and P21/c for Form
in this section. Ib, respectively. The crystal packing analysis suggests that the
Glaser and co-workers, in 1994, reported the molecules in Form Ia are linked into chains by aromatic -
polymorphism and conformational analysis of two rotational stacking interactions whereas this aromatic - stacking
isomers of methyl (para-tolyl) ketone azines using ab initio interactions are absent in Form Ib and instead a C—H  (arene)
calculation and X-ray crystal structures analysis 77.47 Two hydrogen bond is present.
isomers co-crystalized in two monoclinic racemic modification.
Both the rotamers assume the (E,E) configuration in which the
large groups attached to the C=N bonds are trans but they differ
in their conformation across N-N single bond. In the case of
rotamer A, molecule exhibits s-trans conformation (C=N-N=C
torsional angle 180o), while rotamer B exhibits s-gauche
conformation (C=N-N=C torsional angle 142.8°) (Figure 14). The
energy difference between the two rotamers is 0.36 kcal/mol Figure 16. 3D structure of (E,E)-1,4-Bis(2-nitrophenyl)-2,3-diaza-1,3-butadiene
(79).
according to RHF/6-31G*//RHF/3-21G level of quantum
chemical analysis. The authors concluded that “the small Wang and co-workers,124 in 2019, reported the
differences in packing interactions in polymorphous crystals temperature controlling polymorphism and polymorphic
suffice to overcome the intrinsic trans preference”. interconversion in sublimation crystallisation of 5-Methoxy-
salicylaldhyde azine 80 (Figure 17). They demonstrated use of
“an in-air sublimation method for strategically preparation of
two polymorphic crystal forms by controlling sublimation
temperature”. The azine (yellowish powder) was prepared by
the reaction of 2-hydroxy-5-methoxybenzaldehyde with
hydrazine hydrate at 80 °C for 5 h. This yellow powder was
subjected to sublimation using a device consisting of an electric
Figure 14. 3D structures of two rotamers of Methyl (para-Tolyl)ketone azine (77).
hot jacket and a micro sublimator. The polymorph A (exhibiting
orange yellow fluorescence) was obtained as rod like crystals
Amadei et al.,122 in 1998, reported structures of two
when the temperature in the micro sublimator reached 170 °C
polymorphic forms of phenyl 2-pyridyl azine 78. The suitable
and polymorph B (exhibiting weak red fluorescence) was
crystals for the single crystal X-ray diffraction study were
obtained as lamellar crystals at 220 °C (Figure 17).124
developed in methanol by a slow evaporation method. The
white crystals (Form A) and yellow crystals (Form B) were
obtained in 60:40 ratio with an overall yield of 85%. Both forms
are associated with the same Z,Z isomeric state. The authors
reported that “the main crystallographic differences between
the two compounds are” due to the torsional angle across C=N-
N=C framework – 123.4° for Form A (gauche) and 180° for Form
B (s-trans). The orientation of the pyridyl ring also is different in
these two forms. Also, the N-N bond distance is shorter (1.38 Å)
in Form A, in comparision to that 1.41 Å in Form B (Figure 15).
The computational analysis showed that the s-trans conformer
is more stable than gauche conformer by ~2 kcal/mol.
Figure 17. A) 2D structure of 5-Methoxy-salicylaldhyde Azine; B) Fluorescence
microscope images of polymorph 80A and polymorph 80B in the solid state under
UV light excitation (. reproduced with permission American Chemical Society).
The single crystal X-ray diffraction analysis suggests that the

main difference between the two polymorphs is the mutual
orientation of the two methoxy groups corresponds to the
hydroxyl groups. In case of polymorph A, the methoxy and the
hydroxyl groups are oriented in the same directions, and
Figure 15. Form A and Form B of 2-pyridyl ketone azine 78. oriented in the opposite direction for polymorph B. The energy
of polymorph A was found to be 0.94 kcal/mol higher than that
Glidewell et al.,123 in 2006, reported two polymorphs of of polymorph B. DFT study was also employed to explain the
(E,E)-1,4-Bis(2-nitrophenyl)-2,3-diaza-1,3-butadiene 79 (Figure interconversion process between the two forms.
16). The compound crystallizes in two polymorphic forms –Form Recently, our group has reported the polymorphism in
Ia and Form Ib. The crystallographic difference between the two Guanabenz free base 5. The study indicated that E/Z isomerism
forms is clearly visible as the molecules lie across centres of in Guanabenz is responsible for the identification of two

polymorphic forms- Form I i.e. E-isomer (5_E, Entry 1, Table 1) considered to carry the L→N coordination interactions. It is
and Form II i.e. Z-isomer (5_Z, Entry 2, Table 1). The Form I interesting to note that these structural features are known to
crystals adopts block shape whereas Form II adopts rod shape present in many drugs and leads.136
(Figure 18).97 The crystal packing analysis suggested that the
molecules in Form I are arranged in zigzag form whereas in Form
II molecules are arranged in lamellar packing. The differences in
the intermolecular hydrogen bonding and π-stacking
interactions were analysed by quantum chemical analysis and
Hirshfeld surfaces of these two forms.
Figure 19. A) Compounds with central main group elements in their low oxidation
state; B) Triphenyl phosphenazine (84A) and its suggested mesomeric form with
P→N dative bond (84B).
A significant contribution has been made towards the

Figure 18. a) ORTEP diagram of Form I and Form II b) optical pictures of the crystals synthesis and isolation of ligand stabilized diatomic species.
of Form I and Form II. (Reproduced with permission from American Chemical
Society). Such compounds were represented as LE—EL (L=ligand
and E=BH,137, 138 Si,139, 140 Ge,141 P,142 N143 and As144) (Figure 18).
The quantum chemical studies revealed that in the monomeric The electronic structure of azines (C=N-N=C) is gaining attention
state, the E isomer is energetically more stable than the Z in the light of the actual debate about the dative bonding.
isomer by 2.13 kcal/mol, whereas, the under dimeric state, the Wilson et al. carried out a theoretical examination of the LE—
Z isomer is energetically more stable than the E isomer by ~7 EL class of molecules (E = group 14, group 15 element; L = N-
kcal/mol, which suggests that the crystal packing forces might heterocyclic carbene, phosphine). 145 They suggested that in
be the contributing factor for the observation of Form II of complex LE—EL (85, L= 1,3-dimethylimidazole-2-ylidene
Guanabenz.97 and E = N), N2 is stabilized by electron donating NHC. ΔG for the
From the examples and discussion included in this reaction N2 + 2 L→ L-N-N-L is strongly positive with 140 kJ/mol,
section, it became clear that a direct correlation between which is expected to give high thermodynamic stability of N2
structure of molecule at the molecular level and the molecule, suggesting the thermodynamic unstability of such
polymorphic state of the solid material exists, however, the complexes with N2.145
same is poorly understood. Conformational polymorphism is Triphenylphosphenazene (84) represent the first
dominant in azines. Tautomeric polymorphism is also possible dinitrogen system which was considered to carry the P→N
in azines, but not yet reported. The polymorphism reported donor-acceptor bond. This molecule was already known in the
based on E/Z isomeric differences of Guanabenz may be literature (synthesised in 1964 by Appel et al).146 Frenking and
considered as an example of configurational polymorphism. co-workers in 2013 reinvestigated this compound by
computational and X-ray crystallography studies.143 The
8. Bonding aspects in azines computational studies suggested the lower thermodynamic
Compounds in low oxidation state at main group stabilities for the phosphine complexes R3PN2PR3 for which
element (E) are a topic of current interest in synthetic and the calculated dissociation reaction N2(PR3)2 → N2 + 2PR3 is
theoretical organic chemistry. In this context, many organic and exergonic by ~87.8 kcal/mol (R = phenyl) and ~129.9 kcal/mol
inorganic compounds have been taken up for the study from (R = H). The calculated thermodynamic instabilities of N 2(NHC)2
the perspective to reconsider them in the form of stabilisation and N2(PR3)2 are in striking contrast to experimental studies
of main group elements with ligands (Ligand = N-heterocyclic which suggest that triphenylphosphenazene is a stable
carbene in most of the cases). In this direction, many compound which melts beyond 215°C. Based on the quantum
compounds with imine group have been synthesised and the chemical calculations authors described this compound as
possibility of C=N versus C→N coordination bond in these donor-acceptor complex where triphenylphosphine moiety acts
compounds has been explored by experimental and theoretical as an electron donor and dinitrogen (N2) as electron acceptor
methods.125-134 These studies lead to the identification of (Figure 18). The crystal structure data shows it to be dimeric
(L→N←L)+ class of compounds (Figure 19). Compounds with a planar PN2P fragment with P-N-N angles of 107.10°.
with the general structure L→N-R (82) were also reported,129, 135 The geometry optimisation and molecular orbital analysis
in which the L→N coordination bond character is shown to be suggested that the central nitrogen gain two lone pair of
present. Also, species with L(N3)L, (L)3N3+, were electrons due to the donating effect of triphenylphosphene

Journal Nam ARTICLE
moiety. HOMO and HOMO-1 represent the molecular orbitals 9. Redox system in azines
with -type and -type lone pair character.143 Himmel and co- Violenes are violet coloured radical species with the
workers studied urea azines (52, 53, 86-88, Figure 20) to general formula given in Figure 21. They are stable radical ions
understand their redox property and coordination chemistry which derive their stability due to the distribution of odd
with metals.89 They also explored the possibility of CN number of electrons over an even number of atoms arranged in
coordination bond in this class of molecules using experimental a chain. The π-electron delocalisation of a single electron across
and quantum chemical studies. DFT calculations were carried a chain of conjugated double bond provides the intense colour.
out to estimate the enthalpies and Gibbs free energies for the
decomposition of azine into dinitrogen and carbene. The data
suggested the presence of C→N dative bond between
dinitrogen and two carbene atoms. However, the data obtained
Figure 21. General structure of violene with two resonating forms.
from vibrational spectroscopy suggested that the electronic
properties of urea azines are comparable to those of Azaviolenes are also violet coloured species which carry
formaldazine, H2C=N-N=CH2. Therefore, authors concluded that N-N bonds embedded in conjugated radical cation systems (92-
the decomposition energies are indicative of the stability of the 97, Figure 22). Thus azines in their radical cation state are
carbene decomposition products and since the electronic azaviolenes. The redox chemistry of these species was
properties are comparable to those of formaldazine, urea azines extensively explored. However, the bonding characteristic and
52, 53, 86-88 cannot be adequately described in terms of dative electron delocalisation were not thoroughly explored. 147 The
bonding.89 reduced form of the azine (3 Reduced) is reported to undergo
In view of the limited studies on the chemical bonding electron transfer process (Scheme 23). 148-151
across C=N vs. C→N bonds in azines (Figure 19), more studies
are required to explore this concept in detail. Unsymmetrical
azines are gaining importance in organic chemistry, material
chemistry, and medicinal chemistry. In this context, we became
interested in unsymmetrical azines possessing N-heterocycles
such as benzothiazole (89A) due to the importance of this
scaffold in medicinal chemistry. Considering the case of
triphenylphosphenazene (84A) which possess two PN dative
bonds due to the electron donating nature of
Figure 22. Examples of Azaviolenes.
triphenylphosphine, similar (NHC)N bonding situation in
azine 89A between C=N can be expected (Figure 19).
The reduced form of 3 undergoes single electron
Exploration of properties and applications of unsymmetrical
transfer to form radical cation species (3 semiquinone) and
azines is in underway in our laboratory.
upon second electron transfer, forms dicationic species (3
oxidised, Scheme 23). The rate of formation of these species is
determined by oxidation potential calculated from cyclic
voltammetry.148
Scheme 23. Redox system in azine (3).
Studies on azaviolenes proved that reduced form of

azine is basic in nature and thus get protonated easily in the
presence of the acidic medium. In the case of the azine (Scheme
24, 98 reduced) which includes an amidine system, the acid-
base equilibria may be written as in the following Scheme 24. 151
The existence of these species is accomplished by the methods
like EPR, cyclic voltammetry and UV spectroscopy.
Figure 20. Examples of azines studied so far for the possibility of C→N dative
bonds (Reproduced with permission from Wiley-VCH).

assay (Trolox equivalent antioxidant capacity assay, TEAC) was

developed and kits based on the same are being extensively
used to determine the antioxidant activity of any given
species.154
Scheme 24. The acid-base equilibria in azine 98.
Himmel and co-workers in 2015 reported various urea Figure 24. The chemical structure of ABTS, ABTS radical cation (ABTS+) and ABTS dication
(ABTS++). 154
azines/bisguanidines as strong electron donors with the help of
cyclic voltammetry (CV).89 The authors suggested the electron
donating ability of compounds 52, 53, 86-88 (Figure 20) using 10. Applications of azines in medicinal chemistry
CV which showed these compounds can be reversibly oxidized Azines have been investigated for their diverse therapeutic
in two well separated one-electron steps and thus can behave activities. Though only one of them, Guanabenz (5) is a
as strong reducing agents (Figure 23). They also compared the marketed drug (anti-hypertensive agent), several azine
adiabatic ionisation energies (I1) of these species with the I1 of containing compounds exhibited therapeutic potential.155
TDAE (tetrakis(dimethyl ethylamino)ethylene) using Figures 24 and 25 list a few important azines, which were
computational methods. The observed adiabatic ionisation considered for therapeutic applications. The diaminoazines are
energy values are in the order of 88 < 53 < 52, the lower highly basic and hence under physiological condition tend to
ionisation energy of 94 may be attributed towards exist in the protonated state.
intramolecular hydrogen bonding. Compound 53 was also
oxidised with TCNQ which gave the radical salt 53_TCNQ.89
Figure 23. A schematic diagram showing the redox chemistry of urea azines
(reproduced with permission from Wiley-VCH).
2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic Acid)152
(ABTS) acts as a substrate for the enzymatic assay of peroxidase
enzymes. In ABTS/H2O2 peroxidase system, ABTS acts as a
reducing agent that converts the active state (enzyme after
oxidation by H2O2) of the enzyme to its native state (Figure 24).
The colour of ABTS is pale greenish with the max of 340 nm,
whereas ABTS radical cation (highly stable) is green-blue colour
with the max values of 414, 645, 734, and 815 nm. This
oxidation process was utilized indirectly to either calculate the Figure 25. The 2D structures of several medicinally important 1,1-diaminoazines.
amount of hydrogen peroxide produced in the enzymatic
environment or to study the reaction kinetics of hydrogen These diaminoazines in their protonated state have been
peroxide-producing enzyme153 Based on a similar concept, ABTS reported to be useful as lead compounds (Figure 25) in drug

Journal Nam ARTICLE
discovery, the important examples are – the antihypertensive major side-effects. For example, 5 was reported to possess an
agent (5) carrying 2,6-dichloro with 1,1-diamino unit,156 the antiparasitic activity (Toxoplasma gondii) against acute and
trypanocidal agent (99) containing two azine units attached to latent toxoplasmosis. 5 was also found to significantly reduce
pyridine,157 the antibacterial compound (100) with biphenyl the number of brain cysts in chronically infected mice which
ring,158 the antimalarial agent (101) derived from suggests its ability to reduce tissue cysts in the brain. 1675 was
benzophenone,159 the antiseptic known as ambazone (102), the tested in vivo in animal models for the treatment of prion-based
anticoagulant thrombin inhibitor (103) with aryl sulfonyl group diseases (transmissible neurodegenerative disorder) by Blondel
in the side chain,160 and the anticancer species (104-106).161 et al.168 It was found to be active in vivo against yeast and
The non-diaminoazines based lead compounds were mammalian prion. Experiments revealed that the removing of
also reported and a few of them are shown in Figure 26.69 chlorine or replacement of chlorine in Guanabenz with fluorine
Though they are also sufficiently basic, they are reported to be or bromide results in the loss of activity in yeast-based and
showing their therapeutic action as neutral molecules. MovS6-based assays. In contrast, addition of extra chloride in
Naphtho[2,1-b]furan based azines (107) as antibacterial agents, the phenyl ring in 5 increased its activity.168 Voisset et al., in
unsymmetrical azines derived from naphthaldazines (108) are 2014,169 suggested that 5 is also active against both yeast and
antifungal agents,162 bisisatin azine as an anticancer agent mammalian prions but in an independent manner without
(109),163 monoterpene indole alkaloid azine derivatives (110) as affecting α2-adrenergic receptor. Authors performed the
MDR reversal agents.164 Kalinowski et al. reported the structure activity relationship study by modulating 5–5i and 5j
identification of an azine disulfide dimer (111) as an (Figure 27) were found to possess antiprion activity totally
antiproliferative agent (it also exhibits iron chelator property).69 devoid of 2-adrenoceptor agonistic activity.169
Urbanczyk-Lipkowska et al.43 reported the X-ray crystal
structure and biological evaluation of naltrexonazine (44) as
opioid antagonist. Similarly, 14-hydroxy dihydroxymorphinone
azine is also reported as opioid antagonist. 165
Figure 27. The analogous structures of Guanabenz possessing anti-prion activity.
Ristic et al.170 in 2018, reported the synthesis and

biological activity of coumarin based azines as antimicrobial and
antioxidant agents. The synthesised compounds were tested for
their acute toxicities in Artemia Salina. The free radical
scavenging activity of these coumarin based azines were tested
by DPPH assay. The in vitro activity of the compounds was
assessed using various strains of bacteria and fungi. The
compound 112 was found to be best against Staphylococcus
aureus and Acinetobacter baumannii. The compound 113 was
found to exhibit pronounced antioxidant activity (Figure 28).
Figure 26. Biologically active azines, along with their suggested therapeutic
applications. Figure 28. Anti-microbial azines.
Guanabenz (5, (E)-2,6-dichlorophenyl-1,1-diamino-2,3- Jayabharathi et al.,171 in 2007, reported the synthesis and
diazabuta-1,3-diene) is an orally active central 2-adrenoceptor antimicrobial activity of N(1)-arylidene-N(2)-cis-2,6-
agonist used for the treatment of hypertension. The diphenyltetrahydrothiopyran-4-one azine derivatives. The
antihypertensive action of Guanabenz is attributed to result synthesised compounds were evaluated against Bacillus subtilis,
from the reduction in sympathetic outflow from the brain to the Streptococcus faecalis, Pseudomonas aeruginosa, Escherichia
peripheral circulatory system.166 Many researchers are coli, and Staphylococcus aureus and antifungal activity
exploring the possibility ‘repurposing’ Guanabenz for different against Candida-51, Candida-6, niger, Aspergillus
biological activities as it is in clinical use for many years without and Aspergillus flavus. The compounds 114 and 115 (Figure 28)

exerted improved in vitro antibacterial and antifungal activity P. aeruginosa PAO1 and 118 reported to possess the binding
against all the tested strains. A semi-empirical quantum chemical affinity (KD) of 5.7 µM and MIC of 52.3 µg/mL. Further, the in
analysis was performed to validate the stereochemical cellulo HemO inhibitory activity of compounds were carried out
observations obtained through NMR studies. It was found that to access the ability of compounds to inhibit the activity of
the chair conformation with equatorial orientation of phenyl HemO. The compound 118 was found to inhibit HemO activity
groups is the energetically preferred arrangement of the at effective concentration of 11.3 µM measured by biliverdin-
thiopyran ring. dependent IFP1.4 fluorescence. The compound binds to the
In 2013, Liang et al. reported the in vitro and in vivo novel binding site which was proposed using in silico studies and
antitumor activity of bis-Schiff base derivatives of Isatin. 172 A further supported by hydrogen exchange mass spectrometry
series of 18 compounds were synthesised, interestingly more (HXMS) and saturation transfer difference (STD) NMR.175
than half of the compounds were found to be cytotoxic in five
different human cell lines (HeLa, SGC-7901, HepG2, U251 and
A549). Among the promising compounds, bisisatin azine 109
was found to be the most potent against HepG2 cell line with
the IC50 value of ~4.23 µM (Figure 26). The authors have also
studied the effect of 109 on the HepS-bearing mice at a dose of Figure 30. Diaminoazines as hemeoxygenase of Pseudomonas aeruginosa
inhibitor.
40mg/kg. The mechanistic investigation revealed that the
compound 109 arrest the cell cycle in G2/M phase by down Subedi et al. in 2017, reported azines as anti-
regulating the expression of cyclin B1 and cdc 2. 172 neuroinfammatory agents.2 A series of thirteen azines were
Our lab was involved in the design and synthesis of a synthesised from aldehydes and biologically evaluated in LPS-
series of benzothiazole based unsymmetrical azines as quorum activated BV-2 microglial cells. The compounds were found to
sensing (QS) inhibitors targeting LasR.173 The compounds were affect the LPS-mediated neuroinflammation in microglia and
designed based on the reported pharmacophore model174 neuronal apoptosis through inhibiting MAPK signalling
which suggested that the ligands should possess a polar region pathway. Compound 119 (Figure 31) was found to exhibit anti-
linking the aromatic box and hydrophobic box to interact with neuroinflammatory activity with the IC 50 value of 12.47 µM by
LasR. In the designed molecules, the azine group is acting as a protecting neurons from microglia-mediated neurotoxicity.
polar linker joining the benzothiazole (hydrophobic box) and Moreover, it also possesses neuroprotective effect by inhibiting
aromatic ring (aromatic box). The designed compounds were LPS-mediated necrosis and apoptosis, the neuroprotective
synthesised by using one pot method which involves the effect was further supported by FACS analysis. 2
reaction of substituted aldehyde, 3-Methyl-2-
(methylthio)benzo[d]thiazol-3-ium salt and hydrazine hydrate.
The synthesised compounds were preliminarily tested in
Chromobacterium violaceum for evaluating their potential to
inhibit CviR receptor based QS signals. Out of 25 evaluated Figure 31. The structure of most active azine reported as anti-neuroinfammatory
agent.
compounds, 2 compounds (116 and 117) were found to inhibit
>50 % violacein inhibition at 200 µM (Figure 29). The
11. Azines as substrates in the generation of
compounds were further found to inhibit the QS-mediated GFP
heterocycles
signals when tested for LasR receptor based QS using PlasB-
Apart from the application of azines in redox and
gfp(ASV) biomonitor strain of Pseudomonas aeruginosa.
medicinal chemistry, they have been used as a substrate for the
Interestingly, the two active compounds also inhibited biofilm
construction of heterocycles. The reactions of dienophilic
formation at 50 µM concentration.173
compounds with azines represent a valuable enlargement to
synthetic heterocyclic chemistry. Azines have been reported to
undergo criss-cross cycloaddition reaction.176 Azines obtained
from aromatic aldehydes or from hexafluoroacetone are
reported to undergo criss-cross addition with 2 moles of a
dienophile to form 1,5-diazabicyclo[3.3.0]octane derivatives. 10
The chemistry of azines with dienophiles was discussed
extensively in a review published in 1976 by Wagner-Jauregg.10
Safari and Gandomi-Ravandi also discussed a few interesting
cycloaddition reactions of azines. Hence in this section, our
Figure 29. a) Design strategy using suggested pharmacophore; b) active quorum
main focus is to cover reactions of azines which involve the
sensing inhibitors. construction of medicinally important heterocycles such as
oxadiazoles,177 triazoles,178 diazepines,179 pyrazoles180 and
In 2016, Heinzl et al. reported the diaminoazines pyridines.181
(iminoguanidines) as allosteric inhibitors of iron regulated In 1967, Gillis and Lamontagne reported the formation of
Hemeoxygenase of Pseudomonas aeruginosa (Figure 30).175 A oxadiazole by the oxidation of aldazines (120) with lead
series of diaminoazines were synthesised and evaluated against

Journal Nam ARTICLE
tetraacetate (Scheme 25).182 They reported that aldazine upon

treatment with lead tetraacetate gives 1,3,4-Oxadiazolines
intermediate (121), initially via the acetylation of iminic carbon
followed by O to N acyl migration and cyclisation. 121 can be
oxidized to 1,3,4-oxadiazole (122) with lead tetraacetate
(Scheme 25).
Scheme 27. Synthesis of triazole from 4-pyridine-carbaldehyde

(diaminomethylene)hydrazonearomatic with acetic anhydride
Scheme 25. Synthesis of oxadiazoles from aldazines.
In 1995, Györgydeàk et al. reported that aromatic

carbaldehyde (diaminomethylene)hydrazones (123) on
Scheme 28. Synthesis of triazoles from the azines derived from cyclic ketone.
reaction with hot acetic anhydride produce 1,4-diacyl-3-
acylamino-5-aryl-4,5-dihydro-1H-1,2,4-triazoles (124, Scheme Boyle and Grundo in 1967 reported that treatment of
26).183 When 4-pyridine-carbaldehyde benzaldehyde azine (128) with potassium t-butoxide (1-2
(diaminomethylene)hydrazone (125) was treated under the moles) in boiling toluene for 40 hr. resulted in the formation of
same reaction condition, a new type of O,N-acetal with a 1,2,4- 3,5-diphenyl-1,2,4-triazole (129) as the major product and its
triazole substructure (126) was obtained. (Scheme 27). The benzyl derivative (Scheme 29). They suggested that
structures of all novel compounds were confirmed by benzaldehyde azines behave as dipolar species which must
spectroscopic data (1H and 13C NMR, MS, IR). The formation of undergo 1,3-cycloaddition with a second molecule of
triazole heterocycle was further confirmed by X-ray analysis of benzaldehyde azine to form triazole. 185
some representative examples. Authors also explored the scope
of this reaction for the azine obtained from the cyclic ketone
and found the formation of 3-acylamino-1-cycloalkenyl-5-
methyl-1H-1,2,4-triazoles the (127, Scheme 28).184
Scheme 29. Base catalysed synthesis of triazoles from benzaldehyde azines.
Somsak and co-workers in 2015, reported the synthesis

of symmetric 5-aryl-3-C-glycosyl-1,2,4-triazoles (131) and
unsymmetrical 3,5-diaryl-1,2,4-triazoles from amidrazones
(130, Scheme 30).186 The authors tried various reaction
conditions for the transformation of amidrazones
(unsymmetrical azine) to substituted 1,2,4-triazoles. The
reaction under many conditions lead to the formation of
complex mixture of products such as 3,5-diaryl-1,2,4-triazoles,
nitrile, carbohydrazonyl bromide, 4-Alkylideneamino-3,5-
Scheme 26. Synthesis of triazole from aromatic carbaldehyde hydrazone with
disubstituted-1,2,4-triazoles. The success of these attempts
acetylating agent. could be realized when, the bromo derivatives of amidrazones
were treated with NH4OAc. This intramolecular cyclisation
reaction provided biologically important scaffold 3-C-glycosyl-5-
aryl-1,2,4-triazoles.186

reaction mechanism involves the C−H and N−N bond activation

with air as an external oxidant, which led to an efficient
approach towards isoquinoline synthesis.188 Deshmukh et al.
established a similar protocol which involves the cobalt
catalysed C–H/N–N bond functionalisation of ketazines for the
synthesis of isoquinolines.189 The authors suggested that their
method offers various advantages which include – i) high atom
economy, ii) external oxidant free approach; iii) silver salt free
approach and iv) broad substrate scope.
Scheme 30. Synthesis of 3,5-disubtituted-1,2,4-triazoles.
Recently, our lab reported the I2-promoted tandem

intermolecular nucleophile attack / cyclocondensation /
aromatisation of 1,1-diaminoazines for the synthesis of 4-
arylideneamino-5-aryl-3-amino-1,2,4-triazoles (132, Scheme
31).187 The formation of intermolecular cyclized product was
preferred over the expected intramolecular product; this
observation was attributed to the high energy (22 kcal/mol)
Scheme 33. Synthesis of isoquinoline via C-H and N-N bond activation.
demand for the azine to adopt s-cis conformation. This method
for the generation of arylideneamino-triazoles offers certain
advantages such as no requirement of external oxidizing agents, Our group recently reported the formation of 4,5-
base free reaction conditions, short reaction time, wide dihydro-1H-pyrazole-1-carboximidamides when conjugated
substrate scope, use of substoichiometric amount of iodine, and hydrazones were subjected to heating with acid catalyst
moderate to good yield. 187 (Scheme 34).190 To support this observation, experimental and
computational studies were carried out. The studies suggested
that the open chain isomer of conjugated azine undergoes ring-
chain isomerism under an acidic condition to give
thermodynamically more stable ring isomer (136-R) i.e. 4,5-
dihydro-1H-pyrazole-1-carboximidamide. The quantum
Scheme 31. Synthesis of 4-arylideneamino-5-aryl-3-amino-1,2,4-triazoles from
1,1-diaminoazines.
Barluenga et al. in 1987, reported the unexpected

formation of 5,5-disubstituted-5,6-dihydro-4H-1,2-diazepines
(134) when the dihydroxyazines (133) were treated with
aluminium chloride (Scheme 32).179 The diazepines were
isolated as the sole product in excellent yields. These diazepines Scheme 34: Synthesis of dihydropyrazole from conjugated azine.
are important heterocycles and cannot be synthesised easily.
The available literature suggests that the synthesis of 5,6- chemical calculations also suggests the formation of azine
dihydro-4H-l,2-diazepines can be possible by condensation of tautomer as an intermediate which facilitates intramolecular
1,5-dicarbonyl compounds with hydrazine, while the synthesis cycloaddition reaction by the attack of nucleophilic centre N2 to
of the corresponding 5,5-disubstituted derivatives is difficult. the C6 carbon to give ring isomer. The estimated barrier for this
There are only a few examples where the synthesis of this class process was 31.37 kcal/mol.190 Kallitsakis et al.191 recently
of compounds has been discussed, hence, the authors claimed reported the synthesis of a series of new (N'-substituted)-
that the formation of diazepine from azine is an innovative hydrazo-4-aryl-1,4-dihydropyridines (137) via a facile one-pot
contribution. catalytic pathway using azine (138) and propiolate esters as key
starting material and a one-dimensional copper benzotriazole-
based coordination polymer as a catalyst (Scheme 35). It is
intriguing to note that two alkyne groups get inserted across
one of the imine groups of azine in this Cu(II) catalysed reaction.
The authors also reported that in the absence of the catalyst,
the corresponding 5-substituted 4,5-dihydropyrazole (139) was
Scheme 32. Unexpected formation of diazepines from azines
formed in moderate to high yields.
An efficient synthesis of isoquinoline (135) has been

reported recently by Huang and co-workers which involves a
rhodium-catalysed sequential oxidative C−H annulation
reaction between ketazines and alkynes (Scheme 33).188 The

Journal Nam ARTICLE
C-H bond activation (Scheme 37a).195 The attractive feature of

this method especially ortho-olefination of aromatic ketazines
are i) low loading of Rh-catalyst, ii) mild reaction temperature,
iii) high yield and iv) selective E-configuration across olefinic
bond in the products, as well as v) good chemoselectivity.
Recently, the Rh-catalyszed ortho-C-H carbenoid insertion
reaction of diarylazines with diazo compounds has been
developed by Yu et al. (Scheme 37b).196 A wide range of ortho-
substituted diarylazines have been obtained with high
regioselectivity at room temperature.
Scheme 35. Synthesis of 1,4-dihydropyridines and 5-substituted-4,5-

dihydropyrazoles from aldazines.
12. Azines as directing groups

Generally, the main reactions of azines with transition
metal complexes are N–N bond cleavage and coordination of
metal complexes with the azine. 192 Various nitrogen-containing
functional groups have been well explored as directing groups
due to their ability to coordinate with transition-metals.
Recently, azines have been proved to be viable directing group.
Scheme 37 a) Rhodium catalysed sulfuration and olefination; b) Rhodium
The examples depicting the azines as directing functional units, catalysed ortho-C-H carbenoid insertion of diaryl azines.
this new application is presented below where regioselective
alkylation, olefination or sulfuration by activating ortho C-H has 13. Azines in material chemistry
been reported. Material chemistry is a branch of chemistry which deals with
C–C coupling reactions of azine catalysed by Ru 3(CO)12 the generation and application of bulk level properties of
were reported by Donnecke in 2004. 193 When napthaldazine chemicals. In this section, we will systematically discuss the
was treated with ethylene in the presence of Ru3(CO)12 catalyst, application of azines as conducting material, COF, MOF, sensors
the formation of ortho-substituted azines (140) have been and energetic material.
observed in good yield (85%) with the formation of small
13.1. Azines based conducting polymers
amount of side product i.e. ortho-substituted nitriles (Scheme
The first thought about the application of azine as
36a). This is because of the directing ability of azine. Lim and
conducting polymers came when Euler and Hauer reported197
Koo in 2005, reported the rhodium-catalysed alkylation of
the extended Huckel calculation on azine analogue of
aromatic azines.194 They reported the formation of alkylated
polyacetylene where the band gap was calculated. Based on the
products (141) by the treatment of aromatic azines with
value of band gap it was proposed that polyazines198 can act as
terminal alkenes in presence of rhodium catalyst [RhCl(coe) 2]2
poor conductors but oxidative doping could produce a
and Cy3P (Scheme 36b), this example also represents azines as
conducting state in them. Later on, the authors prepared
a viable directing group.
polyazine, (142, −N=C(R1)−C(R2)=N−) as a new class of polymeric
conductor which upon doping with iodine produced air stable
electrically conducting material.199, 200
Chaloner-Gill et al. in 1991201 studied the iodine doped
polyazine and from their study, it was concluded that polyazines
can be oxidized with iodine to form bipolaron charge carriers
(dicationic species). The generation of bipolarons after doping
with iodine has been studied by I5N and 13C NMR spectroscopy.
The spectroscopic techniques clearly showed the presence of
charge on the nitrogens in the form of nitrenium ion (-C=N+=N-
).201 This claim was further supported by molecular orbital
Scheme 36. a) Ruthenium catalysed regioselective C-H activation b) Rhodium calculations on neutral and cationic polyazine model by Dudis et
catalysed alkylation of aromatic azines. al. in 1993.202 The authors explored the various possibilities for
the conductivity mechanism and provided evidenced against
In 2015, Wen et al. described the rhodium-catalysed the mechanism proposed via nitrenium ion. They suggested
sulfuration and olefination of aromatic ketazines via oxidative that oxidative doping of polyazines results into structural

rearrangement or irreversible reaction of the polymer through

nearly collinear diazoalkane like –C=N+=N− moieties (Figure 32).
Figure 32: Neutral polyazine; B) Bipolaron (dicationic species).
As discussed in the previous section, McLoughlin et al. in

2007 carried out quantum chemical studies and suggested that
azine bridge act as a conjugation switches. Authors suggested
that this property of azine make them useful as tunable
molecular devices.203
13.2. Azine based covalent organic frameworks

Covalent organic frameworks (COFs) are a class of crystalline
porous material made up of lightweight elements and
connected by covalent bonds.201 These COF are characterized Scheme 38. Schematic representation of the Synthesis of the azine-linked COF
by the presence of precise periodicity predesignable pore (ACOF-1).
parameter. COFs received much attention due to their potential

use in catalysis, gas storage, optoelectronics and as sensors.204 The crystal structure analysis indicates that ACOF-1 consists of
The presence of strong covalent bond, low density and AA stacking structure, where the pyrene units occupy the
robustness make them different from Metal Organic vertices and the azine (-C=N-N=C-) linkers form the edges of
Framework (MOF). The secondary basic units in COFs are linked two-dimensional (2D) polygon which results in the formation of
by small chains/functional units (linkages) such as boronate, highly luminescent COF. The azine linkers help to accommodate
boroxine, borosilicate, imine, triazine, hydrazone, squaraine, the guest molecules as they possess hydrogen bonding sites.
and borazine have been explored as COF but among them, only The designed COF acts as a chemosensor which can help in the
a few examples of COFs have been reported to show the detection of explosive agent such as 2,4,6-trinitrophenol.206
desirable thermal and chemical stability parameters. Among all, Alahakoon et al. in 2013, reported ACOF-2 which was
boronate linkers (B-O) have been well developed but suffer synthesised from six fold symmetric hexphenyl benzene (HEX-
from disadvantage of rapid decomposition upon exposure to monomer) based aldehyde and hydrazine (Scheme 39).207 The
water vapour or moisture due to their weak chemical stability. ACOF-2 bear narrow pore size distribution and high surface area
Recently, the COFs constructed through the formation of C–N with the average pore size of 1nm and 1200 m 2/g surface area.
bonds have overcome the drawbacks of B-O linked COF. The gas adsorption capacity with ACOF-2 was evaluated which
In this context, Dalpati et al. in 2013 have developed azine shows the excellent sorption capability for CO 2 (20 wt %) and
linked COF which exhibit high crystallinity, high porosity, and CH4 (2.3 wt %) at 273 K and 1 atm.
robust chemical stability (Scheme 38).205 As shown in Scheme
38, the azine linked COF (ACOF-1) can be synthesised by the
condensation of hydrazine with pyrene derived aldehydes
under solvothermal conditions. The stability of the synthesised
COF was evaluated by exposing them to polar as well as non-
polar organic solvents, inorganic acids as well as bases.
Scheme 39. Synthesis of ACOF-2.
Li et al. in 2014, generated new azine linked covalent organic

framework (ACOF-3) for gas storage application (Scheme 40).208
ACOF was synthesised by condensation of hydrazine hydrate
and 1,3,5-triformylbenzene under solvothermal condition.
ACOF-3 carries excellent porosity with a high Brunauer–
Emmett–Teller (BET) surface area of over 1000 m2 g-1. The study
revealed that ACOF-3 can store up to 9.9 mg g-1 of H2, 11.5 mg
g-1 of CH4 and 177 mg g-1 of CO2 at 273 K and 1 atm, with high
selectivity towards CO 2 over CH4, N2.

Journal Nam ARTICLE
Scheme 40. Schematic representation of the synthesis of ACOF-3.
Vyas et al. in 2015 synthesised a series of tunable ACOFs for

visible light-induced hydrogen generation from water.209 ACOF-
4 (Scheme 41) was synthesised by condensation of hydrazine
with triphenylarene aldehydes. The synthesised ACOFs are
photo and water stable. The authors reported the visible light
induced increase in hydrogen evolution with the increase in
nitrogen content of the framework.
Scheme 42. Synthesis of azine-linked pyrene COFs (ACOF-5).
two tautomeric forms i.e. azine and hydrazone in ACOF-5. To

confirm the tautomeric preferences of azine vs. hydrazone in
ACOF-5, a solid-state NMR analysis was performed and the data
was compared to the 15N shifts obtained from theoretical
calculations. Based on the in depth experimental studies,
authors suggested that ACOFs exhibit high CO2 uptake at low
pressures, good selectivity and good uptake under atmospheric
flow conditions and thus are promising candidate for post-
combustion CO2 capture.210
Apart from the examples presented above applications
of ACOF have been reported for the separation of CO 2 from an
Scheme 41. Schematic representation of the synthesis of ACOF-4.
equimolar CO2/CH4 mixture.211
Stegbauer et al. reported the development of isostructural 13.3. Azine based metal organic frameworks
ACOFs and explored their application as sorbent for CO 2 and Metal−organic frameworks (MOFs), are fascinating class of
H2O.210 In their study, they have considered ACOFs based on crystalline porous materials consisting of metal ions and organic
1,3,5-triformyl benzene (ACOF-3) and 1,3,5- linkers.212 Recently, this class of organic frameworks have
triformylphloroglucinol (ACOF-5). An acid catalysed approach gained great attention owing to their unique characteristics
(Scheme 42) was utilised to carry out the condensation reaction such as high surface area, good thermal stability, uniform
between aldehyde and hydrazine. These ACOFs have identical structured nanoscale cavities, uniform and tunable pore size. 213
pore topologies but they differ due to the framework polarities. These properties of MOFs allowed their use for gas storage,
The presence of azine linkage in the synthesised compounds sensing, drug delivery, biomedical imaging, and catalysis.214-216
was confirmed using 13C solid-state NMR MAS spectroscopy. The azine functionalized MOFs have been reported for CO 2
The crystalline nature of these COF was determined using capturing and it was suggested that CO2 uptake by MOFs can be
powder XRD. By the comprehensive structural analysis the achieved by functionalizing the pore of MOFs either by changing
authors reported the co-existence of the metal centre or tuning the basic property of organic part. As
discussed in section 8 (bonding aspect in azines) azines are
highly basic especially the central nitrogen of azine unit contain
excess electron density and hence behave as Lewis base. Many
researchers have

13.4. Azine based energetic material

The key requirements for a particular material to behave
as energetic material are a) high nitrogen content, b) high
density c) high heats of formation, d) low carbon and hydrogen
content, and e) thermolability etc. 222 Interest in the
Figure 33. Chemical structures of organic functionalities utilized for the
construction of MOF. development of energetic nitrogen rich species (explosives or
propellants) has led to the use of azines for the synthesis of
developed azine based MOFs exploiting the idea that azine energetic material.
group on the pore surface behaves as a Lewis base and form In 2011, Klapotke et al.223 reported the synthesis of 1-
strong interaction with acidic CO2 due to complexation. In most diazidocarbamoyl-5-azidotetrazole (143)224 an energetic
of the cases bis(4-pyridyl)-3,4-diaza-2,4-hexadiene (4-bpdh) and material obtained from azine based intermediate isocyanogen
1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene (4-bpdb) (Figure tetrazide (144, Figure 35).223 The single crystal structure was
33)217, 218 were used as organic counterparts. obtained to confirm the structure of 143. The explosive
In 2014, Morsali and coworkers reported the properties such as shock sensitivity, friction sensitivity, heat of
mechanochemical synthesis of MOFs which contain azines (4- formation and nitrogen content were estimated using
bpdb, 4-bpdh, Figure 33) or imine (4-bpmb) and Zn(II) as experimental methods. The shock and friction sensitivity of 143
metal.218 They synthesised three zinc(II) metal−organic was found to be under the limits of 0.25 J in impact and 1 N in
frameworks, two with azine functionality (TMU-4 and TMU-5) friction sensitivity respectively. The heat of formation of 143
(Figure 34). The TMU-4 with the general formula ([Zn2(oba)2(4- was found to be 1495 kJ mol-1 with a high energy content of
bpdb)]·(DMF)x, contains 4-bpdb and TMU-5 with the general 89.08 %.223
formula [Zn2(oba)2(4-bpdh)]·(DMF)y) contains 4-bpdh. The
authors established the use of TMU-4 and TMU-5 for the
removal and extraction of heavy metal ions (such as Co(II),
Cr(III), Cu(II) and Pb(II)) from aqueous samples. It was claimed
that the greater basicity of the azine groups in TMU-4 and TMU-
5 helps in greater interaction with metals and hence greater Figure 35. Chemical structure of 1-diazidocarbamoyl-5-azidotetrazole (143) and
Isocyanogen tetrazide (144).
adsorption efficiency in comparison to related imine based
MOFs.218 Further, the group established the CO2 capture ability In 2015, Wu et al. studied guanylhydrazone substituted
of these MOFs219 and investigated the catalytic application in furoxan derivatives (Figure 36) as thermal stable energetic
Knoevenagel condensation.220 Abbasi et al. deposited TMU-4 and materials. These derivatives were synthesised, characterized
TMU-5 on the surface of silk fibers by exposing them under U.V. and evaluated for energetic properties.225 The structures of a
irradiation. This fibrous material (Zn(II)-MOFs@fibers) was used few of the derivatives were confirmed by single crystal XRD
to remove morphine from aqueous samples due to formation analysis. The thermal stabilities of all the synthesised
of host-guest complexes.221 compounds were evaluated which suggested that except a few,
all the compounds exhibit good thermal stabilities with
decomposition onset temperature above 200 °C. The heat of
formation is found to be in the range of 160 kJ mol−1 (145) to
1214 kJ mol−1 (147). Apart from this detonation pressure values
and detonation velocities were calculated. All these studies
suggested that the compound 145 possess good thermal and
energetic properties among the compounds under study.225
Figure 36. Furoxan based energetic materials.
13.5. Azines as Chemical Sensors

Figure 34. Structure of TMU-4 (azine based MOF).218 The electron density is located on the C=N-N=C
functional group due to which the azine ligands have ability to
bind to metal ions/cations or anions which results in the change

Journal Nam ARTICLE

Figure 38. Chemical structure of azines based chemosensor for Hg2+.
in the fluorescence of the ligand. The chelation enhanced
fluorescence (CHEF) or charge transfer (CT) emission is
In 2010, Suresh et al. reported the quinoline-based
predominantly responsible for the enhancement of
receptor (152, Figure 39) for recognition of Hg2+ Ion.235
fluorescence of chemosensor/ligand in the presence of metal
Coordination of azine to Hg2+ ions induces a colour change and
ions. The criteria for desired chemosensor is sensitivity, quick
a turn-on fluorescence response. The turn-on fluorescence
response time, high selectivity towards analyte and preferable
response is attributed to the complexation/co-ordination
signal-to-noise ratio. The azines have been evaluated as
between lone pairs of nitrogen of quinolone (N1) and nitrogen
chemosensors for various ions such as Hg2+, Cu2+, Cd2+, Zn2+,
of azine (N2) with Hg 2+. The authors suggested the application
Fe3+, CN-, PO43− etc.226-228 The azines have been also evaluated as
of this method in for imaging the accumulation of Hg2+ ions in
pH probe or detection of pH.229 They have been also reported as
Epithelial cell line KB 31 cells.235
electrochemical sensors.230 Mainly, two methods i.e.
colorimetric and fluorescence have been utilized for the
purpose of detection.
Molina and co-workers synthesised ferrocene231 (148)
and pyrene based azines (149).232 The metal binding ability of
compounds 148 and 149 was analysed (Figure 37). The metal
Figure 39. Quinoline derived azine and its Hg2+ complex.
complexing ability of compound 148 was evaluated by
electrochemical and optical analysis whereas, the ability of
In 2011, Dalapati et al. synthesised the symmetrical
compound 149 was evaluated by fluorescence and optical
azines (N,N-Bis(imidazo[1,2-a]pyridine-2-ylmethylene
analysis. The sensitivity and selectivity for Hg 2+ was confirmed
hydrazine, 153, Figure 40) which possess high selectivity
by the addition of Hg(ClO4)2 to a solution of compound 148 in
towards toxic Hg2+.236 This azine sensor which is nearly non-
acetonitrile/water (7:3) which caused the shifting of band from
fluorescent shows enhanced fluorescence on treatment with
476 nm to 521 nm resulted in the change of colour from yellow
Hg2+. More importantly, this sensor help to effectively
(neutral azine 148) to deep purple (complexed azine).
distinguish Hg2+ from Cd2+ or Zn2+ ion due to the different
Alternatively, when Hg(ClO4)2 was added to a solution of
mechanistic pathway – For Hg2+ ion detection chelation
compound 149 the band shifts from 383 nm from 434 nm,
enhanced fluorescence (CHEF) effect works whereas for Cd 2+ or
which is responsible for the change of colour from pale-yellow
Zn2+ ion the charge transfer (CT) mechanism.236
to deep orange. Results from the various analytical tools
suggested that the compounds 148 and 149 are highly selective
chromogenic sensors of Hg2+.232 The same research group
reported 1,4-bis(1-pyrenyl)-2,3-diaza-1,3-butadiene (150) that
can selectively sense Hg 2+ and Cu2+. The change in colour and
the enhancement of fluorescence helps in selectively Figure 40. Structure of Imidazopyridne derived azine.
distinguishing two ions from others. 233
Isa et al. reported the palladium(II)
dichloroacetylthiophene fenchone azine (154) based electrode
for the selective detection of Co 2+ (Figure 41).237
Figure 37. Azines based chemosensors reported by Molina and co-workers.
Figure 41. Structure of palladium(II) dichloroacetylthiophene fenchone azine and

In 2008, Sheng et al. reported the coumarin based azine its Co2+ complex.
(151, Figure 38) as a new colorimetric chemosensor for Hg 2+.234

The authors reported that in the presence of Hg2+ ions the In 2012, Narayanaswamy and Govindaraju developed
absorption maximum of azine shifts from 490 nm to 565 nm (Δ= novel aldazine based chemosensor (Figure 42) for Cu2+ and Fe3+.
238 The salicylaldehyde based azine (155) showed excellent
75 nm) which results in change in colour from orange to purple.
This method helps in distinguishing Hg2+ ions from metal sensitivity towards Cu 2+ which was confirmed by the shifting of
cations such as Fe2+, Co2+, Ni2+, Zn2+, Cd2+, Cu2+, Fe2+, Ag+, Pb2+, absorption band of 155 from 425 nm to 545 nm. After
alkali metal and alkaline earth metal cations. 234 complexation the colour of the solution changed from pale
yellow to purple colour. Similarly, the julolidine based azine
(156) showed high selectivity for Fe 3+ over the other transition
metals. Upon addition of Fe3+ in the solution of 8-
hydroxyjulolidinal-azine the colour of the solution turned to be

violet from pale yellow and the absorption band shifted from
445 to 575 nm.238
In 2013, Ray et al. reported the synthesis of p-N,N-
diethylaminobenzaldazine (157, Figure 42) and the
spectroscopic properties (PDEAB) were analysed using steady
state absorption and fluorescence measurement. The analysis
suggested that the PDEAB forms intermolecular hydrogen bond
with protic solvents which indeed results in the turn-on
fluorescence. The authors suggested that this study helps in
detecting the traces of polar solvent in aprotic medium. 239
Figure 42. Salicyladehyde (155, 157) and julolidine based azines (156) as
chemosensors.
Figure 44. a) Unsymmetrical azine for the detection of cyanide; b) Mechanism of

In 2016, Liu et al. synthesised Ferrocene-based detection of CN-.
unsymmetrical azines (Figure 43) and explored their potential

as multisignaling sensors for Hg2+ and Cu2+ in aqueous Ghosh et al. utilized the naphthalene based and
environment.240 Among the series, two compounds (158, 159) anthracene based azines (163, 164, Figure 45) for the selective
were shown to be excellent chemosensor for Hg 2+ and Cu2+. recognition of Ag+. They also reported the anthracene based
The detection limit for the compound 158 can reach up to 6.77 azine efficiently identify Ag + in rice root tissue infected by
× 10-7 M for Cu2+ and 7.19 × 10-7 M for Hg2+ respectively which endophytic bacteria.245
was quantified using absorption titration analysis. Similarly, for
compound 159 the detection limit is 1.29 × 10 -7 M and 2.40 ×
10-7 M for Cu2+ and Hg2+.240
Figure 45. Azines for the detection of Ag+.
13.6. Azines as NLO material

Figure 43. The 2D structures of Ferrocene-based unsymmetrical azines as NLO is a phenomenon of light which is observed in media
chemosensors for Hg2+ and Cu2+.
due to the non-linear response of the media on the electric
component of light. Many non-linear optical materials
Hu et al. in 2016 developed the azine based sensor (160)
originating from organic compounds have been explored. These
for the selective detection of CN- in aqueous media (Figure
NLO materials are useful in solar cell, photonic devices,
44).241 The chemosensing ability can be analysed by the
electrochemical sensors etc.246-249 This NLO property of organic
colorimetric and fluorescence turn-on responses. The analysis
materials can be fine-tuned by modifying the macroscopic
showed that the compound exhibited colour change from
dipole moments with the help of changes in the substituents in
colourless to yellow colour after the addition of CN - which was
an individual organic molecule. NLO material based on azines
detected by 50 fold enhancement in fluorescence at 530 nm.
were considered for the past twenty five years.94, 250-261
The strong fluorescence appears due to the deprotonation of
Azine possess two acceptor groups (–C=N) oriented in opposite
acidic proton (-O-H) by cyanide ions, which results in the
direction between the para substituted donor and acceptor
breakage of hydrogen bonding and thus release energy due to
aromatic rings makes them an ideal for NLO material. The low
radioactive decay. The LOD for detection of CN- is 6.17 × 10−8
dipole moments and structural components (donor, acceptor
M analysed by titration method.241 Similarly, many research
groups) that favour parallel alignment of dipole moment make
groups have reported the unsymmetrical azines (161, 162,
azines an excellent candidate with nonlinear optical material.
Figure 43) as chemosensors for the detection of CN-.242-244 Centore et al. reported the potential optical nonlinear
electronics of second order in azine derivatives. 251 Glaser and co-
workers reported the effect of symmetrisation on the molecular
organic NLO material with azine frame work.56, 252 They also reported
several studies which includes the structure, stereochemical,
stereoelectronic, synthesis, polar order in crystalline form,

Journal Nam ARTICLE
anisotropic crystalline structure, push-pull effects as well as optical azines, the electron delocalisation properties, the charge
properties of azine based material, thus providing the excellent distribution properties, isomerism (E/Z, tautomerism, and
bridge between the synthesis, electronic, structure and NLO conformational isomerism), reactivity, bonding situation as well
properties of several azine derivatives. 56, 252 as material characteristics (e.g. NLO). The structural features of
Facchetti et al. reported azinium-(π-bridge)-pyrrole these compounds provide large variations, thus, providing
NLO- phores (165, Figure 46) properties and the effect of opportunity for exploring the influence of substituents on the
modulating the heterocyclic acceptors on chromophoric and electronic characteristics. A few of these azine derivatives were
self-assembled (SA) thin layer properties were studied. 254 In the shown to carry important therapeutic applications such as anti-
designed possess, pyrrol-2-yl ring act as primary donor groups hypertensive, anti-parasitic, anti-microbial and anti-cancer.
and -deficient azinium acceptor. The authors suggest that the Guanabenz, an anti-hypertensive drug has been repurposed for
chromophore and SA properties are mainly influenced by the anti-parasitic and anti-prion activity. Many innovative structure
nature of -deficient azinium acceptor.254 Similarly, 1,3-dithiol- frameworks with the help of azine constructs are being
2-ylidene donor-acceptor chromophores containing an azine generated towards the synthesis of N-heterocycles such as
spacer was reported by Moreno-ManÄas.253 Valverde et al. also triazoles, diazepines, pyrazoles, isoquinolines, dihydropyridines
reported the potential application of unsymmetrical azines in and oxadiazoles. The interesting physical characteristics such as
the development of NLO material.94 structural, magnetic and optical properties of azines make them
potential candidates for the design of MOF, COF, conducting
material, sensing material, energetic material, liquid crystals
and NLOs. Apart from these applications, the azine metal
complexes have also been reported extensively in literature.
The contents of this article while indicating the
versatility of azines, lead to many intriguing queries e.g., the
variation exhibited by the structures of azines, leave many
questions unanswered specially regarding conjugation across
the azine framework. The effect of substituents on the
Figure 46. The figure represents the example of azinium-(π-bridge)-pyrrole NLO-
phores. conjugation across C=N-N=C is currently the topic of concern for
the scientific community which needs to be unraveled. The
Recently, Custodio et al. reported the supramolecular approach azine-hydrazone tautomerism in this class of molecules has
to predict the nonlinear optics potential of (7E, 8E)-2-(3- been well studied but there is need to study triple tautomerism
methoxy-4-hydroxy-17-benzylidene)-1-(4-Nitrobenzyliden n)- (azine-azo-hydrazone) using theoretical as well as experimental
hydrazine (166, NMZ, an asymmetrical azine, Figure 47). The methods. Similarly, polymorphism in azines have also been
optical dipole moment (𝜇), the linear polarisation (𝛼) and the reported up to a limited extent and there is scope to explore.
first (𝛽) and second (𝛾) hyperpolarizability were investigated The redox chemistry and the associated electron exchange
which suggest NMZ carries properties of good nonlinear optical characteristics and their influence on the chemical bonding in
material.250 their system needs to be explored. Molecular switching is a
topic of contemporary interest because of their application in
the design of electronics and optical memory devices. The
azines can be used to design the molecular switch material as it
carries the electro- or photo- switchable subunits and thus
exploration is required in this direction. The scope of 1,1-
diaminoazines should be considered for the design of material
Figure 47. Structure of NMZ. such as MOF and COF. The scope of azines as substrate needs
to be considered for the synthesis of heterocycles such as
Apart from the above applications other related application of imidazopyridines, triazines, etc. More importantly, 1,1-
azines are in in liquid crystal, organic field-effect transistor diaminoazine class of molecules can be explored as a substrate
(OFET),257 organic light emitting diodes (OLEDs),262 for Biginelli reaction. Apart from these, limited literature on the
photovoltaic,259 film transistors263 etc. azines as directing group needs to be scrutinized. The limited
literature on this specific class of azines needs to be expanded.
14. Conclusions and Future Perspectives These opportunities shall have a great influence on the
Azines are versatile class of compounds with wide range therapeutic, organic as well as material characteristics of
of applications. In this review, it was established that there are chemicals carrying azine moiety.
several innovative methods of synthesising azine class of
compounds. One of the recent methods involve the formation Conflicts of interest
of azines from the reaction of alcohol with hydrazine hydrate in
“There are no conflicts to declare”.
presence of catalyst such as ruthenium pincer complex, Ni(II)
complex of 2,6-bis(phenylazo)pyridine. Quantum chemical
studies can be efficiently used to obtain the 3D-structures of the

Acknowledgements Notes and references

The authors acknowledge Department of Science and ‡ Footnotes relating to the main text should appear here. These
Technology, New-Delhi, India and Council of Scientific and might include comments relevant to but not central to the matter
Industrial Research (CSIR), New Delhi, India. The authors also under discussion, limited experimental and spectral data, and
thank Prof. Uwe Beifuss, who is a part of a DST-DAAD project crystallographic data.
being executed at NIPER, for useful discussions.
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