Charge transfer facilitated direct electrophilic substitution in phenylaminonaphthoquinones: Experimental, theoretical and electrochemical studies

Article abstract of DOI:10.1039/c3nj01228j

A simple and effective synthetic protocol to introduce electron withdrawing substitutents (Br and NO₂) in the phenyl ring of 2-(p-R-phenylamino)-3-chloro-1,4-naphthoquinones (where R = H, Me, OMe, F and Cl; 1a-e) has been demonstrated using the

Full text of DOI:10.1039/c3nj01228j

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Charge transfer facilitated direct electrophilic
substitution in phenylaminonaphthoquinones:
experimental, theoretical and electrochemical
studies†
Cite this: New J. Chem., 2014,
38, 993
A. Satheshkumar, K. Ganesh and Kuppanagounder P. Elango*
A simple and effective synthetic protocol to introduce electron withdrawing substitutents (Br and NO2)
in the phenyl ring of 2-(p-R-phenylamino)-3-chloro-1,4-naphthoquinones (where R = H, Me, OMe, F
and Cl; 1a–e) has been demonstrated using the phenomenon of intermolecular charge transfer (CT)
complexation as a catalyst. These compounds were subjected to direct bromination (using Br2) and
nitration (using NO2BF4) in the presence of hexamethyl benzene (HMB) as an electron donor partner in
the formation of CT complexes with 1a–e. The results indicated that the quinone–HMB adduct is more
susceptible to direct electrophilic substitution than the quinone alone. It was observed that there is a
tremendous increase in the yield of the products. 1H and 13C NMR, 1H–H COSY, 1H NOSEY and LC-MS
spectral analysis of the products indicated that the directing influence of the NH group plays a major
role in determining the orientation in the substitution reactions. Density functional theory and electro-
chemical studies were also carried out to substantiate the proposed mechanism. A preliminary study on
the anti-oxidant and anti-bacterial properties of the reactants and the products was also carried out.
Received (in Montpellier, France)
7th October 2013,
Accepted 6th December 2013
DOI: 10.1039/c3nj01228j
www.rsc.org/njc
or by nucleophilic substitution of 2,3-dichloro-1,4-naphthoquinone.
High yield of the corresponding 2-aminonaphthoquinones can be
Introduction
Quinones are a class of compounds of substantial pharmacological obtained when primary and secondary aliphatic amines/anilines
and toxicological interest. Many synthetic and natural organic substituted with electron donating groups are used. However,
compounds containing a quinone moiety in their structure have amines with electron withdrawing groups afford poor or no yield.11
been used as antituberculosis,1 anti-tumor,2 molluscicide,3 The aryl bromo compounds have been used as potent anti-tumor,
cytotoxic4 and antibacterial agents.5 They have also found antibacterial, antifungal, antineoplastic, antiviral and antioxidant
widespread industrial applications in color chemistry, hair agents.12,13 Brominated aromatic compounds have gained
dyeing,6 photosensitizers7,8 and anion sensors.9 Two primary increasing attention as versatile intermediates for the organic
mechanisms have been proposed to account for the pharmacology synthesis. These halides also undergo carbon–carbon bond
and toxicity of quinones. Quinones can act as electrophiles via formation via cross-coupling reactions such as Stille,14
1,4-addition chemistry leading to covalent modification of Suzuki,15 Heck,16,17 and Sonagashira18 or carbon–hetero atom
biological molecules at their nucleophilic sites. Alternatively, bond formation via aromatic functionalization.
quinones are highly redox active cycles with their semiquinone
A review of literature revealed that no simple method has
radicals, leading to the formation of reactive oxygen species. been reported for the direct amination of 1,4-naphthoquinones
The degree to which these properties contribute to their overall with electron withdrawing substituted aryl amines with good
biological activity is reported to be highly dependent on their yield.11 The nitro derivatives of napthoquinones have the
chemical properties.10
application of anticancer agents,19 hence the synthesis of these
The synthesis of aminonaphthoquinone is usually achieved quinones is unavoidable. But the classical approach to such
either by Michael 1,4-addition of amines with 1,4-naphthoquinone compounds was unfeasible due to weak basicity of the amines.
Although 2-nitroarylamino-3-chloro-1,4-napthoquinones have been
recently synthesized via direct mixed acid nitration of 2-arylamino-
Department of Chemistry, Gandhigram Rural Institute (Deemed University),
3-chloro-1,4-napthoquinones, the yield and generality of the
Gandhigram 624302, India. E-mail: drkpelango@rediffmail.com;
method are limited.20 The direct amination of 2,3-dichloro-1,4-
Fax: +91 451 2454466; Tel: +91 451 2452371
napthoquinone with nitro substituted aryl amines was achieved
by using a palladium catalyst and a strong base, which results in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3nj01228j
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poor yield of certain derivatives and also the methodology is
costlier.21
It is well established that all electrophilic aromatic substitu-
tions occur via the formation of p- and s-complexes as sequential
intermediates as shown below.22
In the formation of an initial p-complex (charge transfer complex)
the aromatic ring acts as an electron donor and the electrophile as
the electron acceptor. The formation of such complex is the driving
force for the electrophilic substitution reaction to occur. The rate of
the reaction will depend upon the ease with which the CT complex is
formed. Thus the slow or no electrophilic substitution in the phenyl
ring of the compounds (1a–e) under investigation may be due to the
fact that the existence of intramolecular charge transfer (ICT)
transition between the N-atom and the electron deficient quinone
moiety (n - p*)23 might have removed the electron density of the
phenyl ring and consequently reduced the intensity of formation of
a p-complex with the electrophile.
Scheme 1 Conventional synthesis of 2a–e, 3a–3e.
These compounds were characterized using various spectral
techniques and the results are collected in ESI.† Bromination of
1a–e was carried out in chloroform using bromine (Br2)
(Scheme 1) and the percentage yields obtained are collected
in Table 1. The results indicated that the yields obtained are
very low (9–26%) even after 12 h.
Nitration of 1a–e was carried out in acetonitrile using
NO2BF4 and the percentage yields obtained are collected in
Table 2. The results indicated that the percentage yields
obtained are very low (10–40%) even after 12 h.
Hence, it is presumed that by some means if we are able to
restore the electron density on the phenyl ring, we can make it
relatively more susceptible to electrophilic attack through p-complex
formation as shown above. Recently we have demonstrated that
the imine forming ability of 2,3-diamino-1,4-naphthoquinone
with aldehydes has dramatically been enhanced by the addition
of an external electron donor, hexamethylbenzene (HMB), via
the formation of an intermolecular CT complex between the
quinone and HMB.24 Therefore, in the present endeavor also we
have demonstrated a similar simple and effective charge transfer
facilitated method for the direct bromination and nitration of
2-phenylamino-3-chloro-1,4-naphthoquinones (1a–e) with good
yield, which is otherwise a reaction with very poor yield.
As stated in the introduction section, it is presumed that the
low yields obtained may be due to the fact that the existence of
intramolecular charge transfer transition (ICT) between aniline
and quinone moieties might have reduced the electron density
on the aniline moiety and thereby made the electrophilic
substitution (bromination/nitration) sluggish. The results in
Tables 1 and 2 also indicated that the yield of bromination and
nitration in compounds with electron withdrawing substituents
(1d–e) is relatively low, as expected. Therefore, if, by some
means, we overcome or reduce the intensity of ICT, we could
make the aniline ring relatively electron rich and consequently
the electrophilic substitution easier.
Hence, an attempt was made to use formation of an inter-
molecular charge transfer complex of the quinone by adding
As the biological activity of quinones largely depend upon
the substituents present in them and consequently the redox
chemistry of the molecules,10,25 we have also investigated the
electrochemical behavior of these quinones possessing electron
withdrawing bromo and nitro substituents and the antioxidant
and antibacterial properties of these compounds.
Table 1 Bromination of 2-phenylamino-3-chloro-1,4-napthoquinones
(1a–e) in chloroform in the absence and presence of HMB
Absence of HMB
Presence of HMB
Compound
Time (h)
Yield (%)
Time (min)
Yield (%)
Results and discussion
1a
1b
1c
1d
1e
12
12
12
12
12
20
26
17
11
09
30
20
30
60
60
90
97
93
78
77
The starting compounds, 3-chloro-2-(p-R-phenylamino)-1,4-
naphthoquinones (1a–e; Cl–PANS) (where R = H, Me, OMe, F,
and Cl) were prepared and purified by a reported method.26
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Table
2
Nitration of 2-phenylamino-3-chloro-1,4-napthoquinones
(1a–e) in acetonitrile in the absence and presence of HMB
Absence of HMB Presence of HMB
Compound
Time (h)
Yield (%)
Time (min)
Yield (%)
1a
1b
1c
1d
1e
4
4
4
6
8
36
28
40
24
10
35
35
30
60
60
95
93
96
91
92
hexamethyl benzene (HMB) to reduce or overcome the ICT and
thus render the aniline moiety relatively more susceptible to
electrophilic substitution reaction. The selection of HMB is
based on the fact that it is a well known p-electron donor in a
CT complex formation with quinone acceptors and also it is
chemically inert towards either of the reactants.27 The yields
obtained in the bromination and nitration of 1a–e, in the
presence of HMB, are also given in Tables 1 and 2, respectively.
Interestingly, the results indicated that, our perception is correct
and the catalytic role of intermolecular CT complexation in the
substitution reaction and the effect of substituents on the orienta-
tion of the products are discussed in the following sections. The
quinone–HMB CT-adduct was found to be a best reagent for
substitution in terms of reaction time and percentage yields.
Fig. 2 Change of UV-Vis absorption spectrum of 1a on incremental
addition of HMB.
exhibited hypochromic shift when compared to the parent
(R = H; 1a).29,30 A plot of 1/lmax versus the Hammett’s substituent
constant (sx)31 yielded the following regression equation.
1/lmax = 1.18 Â 10À4 sx + 0.002 (r = 0.97; n = 5)
Such a good correlation indicated that the absorption maximum
of ICT transition is substituent dependent. Also, the positive
reaction constant (r = 1.18 Â 10À4) obtained supported the above
observation regarding the shifts in the lmax values with a change in
the nature of the substituent. Electronic spectral studies revealed
that an incremental addition of HMB to 1a resulted in decrease in
intensity of the ICT band (Fig. 2). This may be due to the formation
of a CT complex between HMB and 1a.
From the concentration variation studies, the formation
constant of the CT adduct was calculated as reported earlier.32
The formation constant for the formation of the 1a–HMB CT
adduct was found to be 2100 L MÀ1. The formation of such a CT
adduct between 1a and HMB was also studied using fluores-
cence spectra. It was observed that the fluorescence emission of
HMB, at 305 nm, was quenched by the addition of 1a (Fig. 3), as
a result of formation of a CT complex between them.33 The
stoichiometry of the interaction between 1a and HMB was
determined by Job’s continuous variation method34 and was
found to be 1 : 1 (Fig. S1, ESI†).
UV-Vis and fluorescence spectral studies
With the aim of investigating the mechanism of formation of
an intermolecular CT adduct between the quinone and HMB
electronic spectral studies were carried out. The UV-Vis spectra
of 1a–e were recorded in acetonitrile and a representative
spectrum is shown in Fig. 1. The lower energy broad band that
appeared in the visible region, centered at 480 nm, corresponds
to n–p* transition (ICT).23,28 The absorption maximum of this
peak was found to depend on the nature of the substituent
present in the aniline moiety.
The electron donating substituents bathochromically shift the
absorption maximum while the electron withdrawing substituents
Theoretical study
With an aim to shed some light on the energy requirements for
the intra and inter-molecular CT transitions discussed above the
frontier molecular orbitals (HOMO and LUMO) and their energies
were computed using the density functional theory using the
Becke 3LYP hybrid functional, by using a basis set of 6-31G.35 The
energy required for the CT transition DE(= EHOMO À ELUMO) for a
representative case is shown in Fig. 4. For other compounds they
are given in Fig. S2–S5 (ESI†). It is evident from Fig. 4 that the
energy required for the ICT transition to occur in 1a was found to
be 2.6901 eV. However, in the quinone–HMB adduct, the energy
required for the intermolecular CT transition to occur between the
Fig. 1 UV-Vis spectrum of 1a.
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further supported by the result that the Mulliken charge on the
C-atoms of the phenyl ring is relatively more in the quinone–
HMB adduct than that in free 1a–e (Tables S1 and S2, ESI†).
Furthermore, it was observed that addition of HMB to 1a–e,
prior to the electrophile, significantly increases the product
yield and reduces the reaction time but doesn’t alter the
mechanism of the reaction. i.e. addition of HMB only alters
the electron density of the phenyl ring.
Mechanism of bromination/nitration and orientation of the
products
Based on the foregoing experimental and theoretical results
and discussion the following plausible mechanism has been
proposed for the bromination/nitration of 1a–e (Scheme 2).
The progress of the reaction, as monitored by TLC, indicated
that the bromination of 1a–e yielded only one product. It is
observed that both in the absence and presence of HMB same
products were formed. The products were characterized by
using various spectral techniques such as UV-Vis, 1H NMR,
13C NMR, 1H–H COSY and LC-MS (see the Experimental section).
Based on the results of the spectral analysis of the products
(2a–e and 3a–e) the orientation in the bromination has been
ascertained and depicted in Scheme 3.
Fig. 3 Fluorescence quenching between HMB and 1a in acetonitrile at
298 K.
The orientation of the bromination products may be deter-
mined by the directing influence of the NH or R or both the
groups. The above scheme indicated that during bromination
in the case of the parent compound (1a; R = H) and compounds
with electron donating substituents (1b; R = Me and 1c;
R = OMe), dibromo derivatives were formed. While in the case
of compounds with electron withdrawing substituents (1d;
R = F and 1e; R = Cl), only mono substituted derivatives were
formed. 1H NMR spectral data for the product (2a) indicated
that when R = H (1a), dibromination occurred ortho (C2 or C6)
and para (C4) to the NH group. This is further confirmed by the
1H–H COSY spectrum (Fig. 5). In the case of methyl substituted
compound (1b), disubstitution occurred ortho (C2 and C6) to the
NH group. Interestingly, in the case of the methoxy substituted
compound (1c), in the dibromo product formed, bromine is
attached to the C-atoms that are ortho to both NH and OMe
groups. The difference observed between methyl and methoxy
substituted compounds is due to the fact that the methoxy
Fig. 4 Frontier molecular orbitals of 1a and 1a–HMB and their DE values.
partners (p - p*) is only 2.2746 eV. Such a relatively less DE group being a stronger electron donating group than methyl, its
value suggested that the intermolecular CT transition between directing influence also played a significant role in addition to
the quinone and HMB is energetically more favored than the that of the NH group in governing the orientation.
ICT in free 1a. Hence, addition of HMB to 1a reduces the ICT
In the case of compounds with electron withdrawing groups
transition via the formation of a quinone–HMB CT adduct. (1d–e), only mono bromination occurred ortho to the NH group.
This is supported by the observations made in the electronic The above results indicated that the directing influence of the
spectrum of 1a with incremental addition of HMB (Fig. 2). Also, NH group played a major role in determining the orientation in
in the quinone–HMB CT adduct, the DE value of the ICT the bromination and in the case of the methoxy substituted
transition was found to be 3.6801 eV which is relatively larger compound, its directing influence was also found to be operational
than that in free 1a. This is in line with our perception, in addition to that of the NH group. Regarding the time taken for
formation of the quinone–HMB CT adduct makes the phenyl the completion of the reaction and percentage yields obtained
ring relatively more electron rich (by decreasing the ICT transi- (Tables 1 and 2), the results obtained are as expected. The
tion) and consequently favors the formation of a p-complex compounds with electron donating groups reacted in a shorter
with the electrophile (Br+ or NO2+ in the present study) which is time with relatively higher yields than those with electron
the prerequisite for the substitution reaction to occur. This is withdrawing substituents.
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Scheme 2 Mechanism of CT assisted electrophilic substitution of 1a–e.
Scheme 3 Bromination and nitration of 1a–e.
The effect of the substituent (R) present in the aniline and 13C NMR spectral studies. The results of mass spectral
moiety on the number and orientation during the nitration of analysis indicated that, irrespective of the nature of the sub-
1a–e was investigated. The nitro derivatives (3a–e) formed in stituent present, in all cases the mono nitro derivative alone is
1
1
the reaction were analyzed using LC-MS, H NMR, H NOSEY formed. Also, as observed in the bromination reaction, addition
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Fig. 6 Cyclic voltammogram of 1 mM 1a in 0.1 M tetrabutyl ammonium
perchlorate in ACN obtained in a glassy carbon electrode at a scan rate of
100 mV sÀ1
.
The following electrochemical parameters were determined from
the voltammetric curves.29,30
E1/2 = (Epa + Epc)/2
DEp = Epa À Epc
Fig. 5 1H–H COSY of 2a.
where Epa and Epc are the anodic and cathodic potentials,
respectively.
of HMB doesn’t alter the nature of the product but only
enhanced the yield obtained. NMR spectral analysis indicated
that, in the case of the parent compound (R = H; 1a), nitration
occurred para to the NH group (at C4). While in all other cases,
whether R is an electron donating or withdrawing substituent,
nitration occurred ortho to the NH group i.e. at C2. These
observations suggested that the ortho–para directing influence
of the NH group is the dominant factor which determines the
position of the incoming nitro group in these products (3a–e).
This is because when both groups are ortho and para directing
and they are in opposition, the more strongly activated one
controls the orientation.36 To further confirm the products
formed in the nitration reaction, as a representative case, the
1H NOSEY spectrum of 3b was recorded (see ESI†).
The values thus obtained (along with ipa/ipc, where ipa and ipc
corresponds to the anodic and cathodic current, respectively)
are collected in Table 3. The E1/2 values of 2-( p-R-phenylamino)-
naphthoquinone (PAN), reported in the literature,29 are also
collected in Table 3 for comparison. The values of ipa/ipc are
close to one suggesting the reversibility of the redox process.
The values of DEp are close to the theoretical value of 60 mV
reported for an one electron reversible system.37 The E1/2 values
of 1a–e are much lower than those of the corresponding PAN29
indicating the more electron deficient nature of Cl–PAN com-
pounds when compared to PAN,29 as expected. Such a lower E1/2
value is due to the presence of a chlorine atom (+I effect)
directly attached to the quinone. This result suggested that
the ease of reduction of quinone can be influenced by the
Electrochemical studies
Table 3 Electrochemical parameters and the longest wavelength absorp-
tion band of the reactants and products
In order to study the effect of substituents on the electronic
perturbation in the phenyl ring, the electrochemical behavior
of the Cl–PANs (1a–e) and the corresponding brominated
products (2a–e) was investigated. The cyclic voltammograms
of these compounds were recorded at room temperature using a
glassy carbon working electrode and 0.1 M tetra butylammonium
perchlorate as the supporting electrolyte in acetonitrile. The
voltammograms recorded in the potential range of +1500 to
À2000 mV yielded two reversible waves corresponding to the
redox process of the quinone ring.28,30,31 A representative
voltammogram is depicted in Fig. 6. The first wave is attributed
to the addition of an electron to the quinone (Q) to produce a
semiquinone radical anion (QꢀÀ) and the second wave corre-
sponds to the subsequent addition of an electron to the semi-
quinone radical anion to give a hydroquinone dianion (Q2À).29,30
a
E1/2 (mV)
ipa/ipc
DEp (mV)
E1/2 (mV)
Wave Wave Wave Wave Wave Wave Wave Wave
Entry lmax
I
II
I
II
I
II
I
II
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
479 À457 À1006 0.90 1.20 74
487 À478 À1080 0.84 1.35 71
491 À510 À1060 0.92 1.15 70
476 À416 À856 1.04 1.35 76
477 À403 À957 0.83 1.19 66
443 À417 À943 1.00 1.23 76
457 À455 À1075 0.98 1.23 71
452 À408 À946 0.98 1.17 78
453 À402 À958 0.83 1.19 66
453 À385 À910 0.99 1.32 69
453 À746 À1232 0.93 0.07 56
84
80
76
74
76
73
79
81
76
60
80
À1209 À1685
À1216 À1773
À1236 À1809
—
—
À1173 À1608
—
—
—
—
—
—
—
—
—
—
—
—
a
Electrochemical properties were taken from ref. 29.
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Fig. 7 Plot of sp against DE1/2
.
substituent present in the phenyl ring as well as the substituent
which is directly attached to the quinone ring. In the present
study, based on the similarities in the voltammetric measure-
ments, we assumed that all the quinones (1a–e) are reduced by
the same mechanism.28,29
Scheme 4 Hybridisation of Cl–PAN according to the electronic proper-
ties of the substituent.
The results in Table 3 indicated that the effect of the
substituents on the reduction process is clearly visible. The
electron donating groups (Me and OMe) shift the E1/2 to more
negative values i.e. made the reduction of the quinone more
difficult while the electron withdrawing ones (F and Cl) made
the reduction of the quinone relatively easier when compared
to the parent compound (R = H). In order to quantify the effect
of substituents on the redox behavior of the quinone, an
attempt was made to correlate DE1/2 (=E1/2(x) À E1/2(H)) values
of the first wave versus the Hammett’s substituted constants
(Fig. 7).31
The good correlation (r = 0.98) obtained indicated that the
substituents in the phenyl ring quantitatively influence the
redox behavior of the compounds. The positive slope obtained
indicated that an increase in the electron withdrawing nature of
the substituents makes the reduction of the quinone relatively
easier as spelt above. The results of the correlation analysis also
indicated that, even though the substituents are not directly
conjugated with the quinone moiety, their effect on the electro-
chemical behavior of the compounds was evident.
of the quinone (possessing electron donating substituents 2a–c)
easier, as expected. However, in the case of quinones with
electron withdrawing groups (2d–e), bromination doesn’t cause
any significant change in the easiness of the electroreduction.
This may be due to the fact that the perturbation of electrons by
the electron withdrawing substituents in 1d and 1e might have
reached a maximum level. And thus the introduction of more
number of electron withdrawing bromo groups (2d–e) doesn’t
alter the reduction potential values significantly. In the case of
nitrated products (3a–e), the observed cyclic voltammograms
indicated that the nitro group is also electroactive in the cathodic
zone studied. A representative voltammogram is shown in Fig. S6
(ESI†). As the reduction potentials of the nitro and quinone moieties
are unfortunately similar, differentiation of the independent stages
from the overall reduction process becomes difficult. Thus, no
attempt was made to analyze the voltammetric behavior of the
nitrated products (3a–e).29,38
Anti-oxidant activity
The quantitative effect of the substituents on the electro-
reduction of the quinone ring suggested that, in the case of As spelt in the introduction section, the pharmacology and
electron donating substituents the resonance effect may be toxicity of quinones largely depend on their chemical structure.
dominant than the inductive effect of the substituent. While This is due to the fact that these activities depend on the redox
in the case of electron withdrawing groups the reverse may be behavior of the quinone which in turn is susceptible to the
true. Based on the observations the following resonance hybrid substituent attached to it, as evidenced from the electrochemical
structures of Cl–PAN have been proposed (Scheme 4).29,30
studies enumerated above. Such biological studies with aryl amino-
The results of the electrochemical studies corroborate well naphthoquinones possessing electron withdrawing substituents
with the percentage yields obtained in both the electrophilic are very rare in the literature, as they are difficult to prepare.
substitution reactions. That is the yield obtained in the bromination
In the present study electron withdrawing substituents
and nitration of the compounds with electron donating substituents (Br and NO2) have been directly introduced into 2-phenylamino-
was found to be relatively higher than those with electron with- 3-chloro-1,4-naphthoquinones by making use of the catalytic role of
drawing groups (Tables 1 and 2). From the results presented in the intermolecular CT process. Hence, a preliminary attempt was
Table 3, it is interesting to note that, after bromination, introduction made to investigate the anti-oxidant properties of the products. The
of an electron withdrawing bromo group made the electroreduction antioxidant activities of Cl–PANs (1a–e), brominated (2a–e) and
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Conclusion
To conclude, a simple and effective method for the direct
bromination and nitration of 2-(p-R-phenylamino)-3-chloro-
1,4-naphthoquinones has been demonstrated by adding an
external inert electron donor, hexamethylbenzene. The added
HMB was found to increase the electron density on the aniline
ring by forming an intermolecular charge transfer complex
with the electron deficient quinone moiety. In other words,
formation of such an intermolecular CT complex reduces the
intensity of intramolecular CT transition between the aniline
and quinone moieties and thereby increased the electron
density of the aniline ring. The proposed intermolecular charge
transfer assisted synthetic protocol works well for the introduc-
tion of electron withdrawing substitutents in the phenyl ring of
1a–e which are otherwise difficult to make. Various spectral
and electrochemical studies were used to find out the number
and orientation of the incoming electrophile in the products
formed.
Fig. 8 Anti-oxidant activity of the reactants and products.
nitrated (3a–e) derivatives were measured by using the DPPH
radical quenching method employing a spectrophotometer.39
For that two different concentrations (20 and 50 mM) of the
sample solutions were added to DPPH solution (100 mM) in
ethanol. After incubation at room temperature for 30 min, the
absorbance of these solutions was measured at 517 nm. The
experiments were performed in comparison with ascorbic acid
and a-tocopherol, known anti-oxidants. The radical scavenging
activity was expressed as follows:
Experimental section
Materials and methods
All the reagents were of commercially available high purity
grade and were used as received. Commercially available
spectroscopic grade solvents (Merck, India) were used as
received. The electronic absorption spectra were recorded on
a JASCO (V 630, Japan) UV-Vis double beam spectrophotometer
using 1 cm matched quartz cells by using the corresponding
pure solvent as reference. The temperature of the cell holder
was controlled with a water flow (Æ0.2 1C). The steady state
fluorescence spectra were obtained on a JASCO (FP 6200, Japan)
spectrofluorimeter. The emission slit width (5 nm) and the scan
rate (250 nm) were kept constant for all of the experiments.
FT-IR spectra were recorded on a JASCO (FT-IR 460 Plus, Japan)
spectrometer. 1H NMR spectra were recorded at Madurai
Kamaraj University, Madurai, on a Bruker NMR spectrometer
(300 MHz, Switzerland). The LCMS spectra were recorded at the
University of Hyderabad, Hyderabad on a Shimadzu LCMS 2010
with an ionization potential at 70 eV, (ESI,† Method) (LCMS
2010, Japan). The geometry optimizations were carried out
using B3LYP exchange functional with 6-311G basis sets using
Gaussian 03 package.41
DPPH scavenging activity (%) = (Ac À As)/Ac  100
where, Ac and As are the absorbance of free DPPH and the
sample, respectively. The results obtained are shown in Fig. 8.
The results revealed that introduction of the electron with-
drawing substituents altered the radical scavenging assay (RSA) of
the compounds. The parent compounds (1a–e) which exhibited
less activity, have shown moderate (RSA > 40%) to significant
(RSA > 50%) activities after bromination and nitration.
Antibacterial activity
A preliminary study on the antibacterial activity of the reactants
(1a–e) and the brominated (2a–e) and nitrated products (3a–e)
against five bacterial strains (Staphylococcus aureus, Streptococcus
mutans, Pseudomonas aeruginosa, Escherichia coli and Klebsiella
pneumoniae) were also carried out using the well diffusion assay
method.40 The given samples were prepared in mg mlÀ1 concen-
tration. In this technique, test organisms which are cultured
overnight were used. Required wells each of 5 mm diameter were
made in the Muller Hinton agar plates and 100 ml of the samples
were transferred into each well. The plates were incubated for
Synthesis
General procedure for the preparation of Cl–PAN compounds
24 h at 30 1C and examined for a clear inhibition zone around (1a–e)26. To a stirred solution of 2,3-dichloronaphthoquinone
the well. The assay was carried out in duplicate for all the test (0.0053 mmol) in water p-substituted aniline (0.0053 mmol) was
organisms. The results of in vitro antibacterial properties are added. The reaction mixture was stirred at 50 1C for 12 h. The
collected in Table S3 (ESI†) and the zone of inhibition is shown progress of the reaction was monitored by thin layer chromato-
in Fig. S7 (ESI†) for Staphylococcus aureus as a representative graphy (TLC). Finally the reaction mixture was filtered through the
case. The results indicated that these compounds exhibited filter paper; the residual solid was dried under vacuum. The yields of
varied antibacterial properties. In general, introduction of an the red color powder obtained were 90–99%. The Cl–PANs
electrophile increased the antibacterial activity of the com- obtained were characterized using various spectral techniques
pounds in 2a–e and 3a–e.
and the results are given below.
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1
2-Chloro-3-(phenylamino)naphthalene-1,4-dione (1a). H NMR (d, 2H, J = 7.5 Hz), 7.94 (m, 2H), 7.56 (s, 2H), 2.34 (s, 3H). 13C
(DMSO-d6) d 9.31 (s, 1H), 8.04 (d, 2H, J = 7.5 Hz), 7.89 (m, 2H), NMR (75 MHz, DMSO-d6) d 179.10, 176.21, 143.25, 140.42,
7.34 (t, 2H, J = 7.8 Hz), 7.15 (d, 3H, J = 6.6 Hz).
135.21, 134.52, 133.36, 131.94, 131.56, 129.51, 126.61, 126.17,
13C NMR (DMSO-d6) d 180.07, 176.63, 143.09, 138.79, 134.79, 123.80, 111.86, 19.82. LC-MS m/z (M + H)+ calcd 455.0;
133.13, 131.92, 130.22, 127.87, 126.47, 126.04, 124.33, 123.92, found: 455.9.
114.22. LC-MS m/z (M + H)+ calcd 283.7, found 284.1.
2-Chloro-3-(2,5-dibromo-4-methoxyphenylamino)naphthalene-1,4-
dione (2c). 1H NMR (DMSO-d6) d 9.12 (s, 1H), 8.04 (d, 2H, J =
2-Chloro-3-[(4-methylphenyl)amino]naphthalene-1,4-dione (1b).
7.5 Hz), 7.90 (m, 2H), 7.65 (s, 1H), 7.38 (s, 1H), 3.90 (s, 3H). 13C
NMR (75 MHz, DMSO-d6) d 179.36, 176.47, 154.33, 143.79, 134.91,
133.20, 132.72, 131.86, 131.71, 131.51, 129.83, 126.49, 126.05,
121.29, 115.38, 112.64, 108.86, 56.92. LC-MS m/z (M À H)À calcd
471.5; found: 469.9, 471.1.
1H NMR (DMSO-d6) d 9.25 (s, 1H), 8.04 (d, 2H, J = 7.8 Hz), 7.88
(m, 2H), 7.13 (d, 2H, J = 8.1 Hz), 7.04 (d, 2H, J = 8.1 Hz). 13C NMR
(DMSO-d6) d 180.09, 176.55, 143.16, 136.11, 134.79, 133.78,
133.09, 131.95, 130.12, 128.38, 126.47, 126.02, 124.09, 113.29,
20.49 (CH3). LC-MS m/z (M + H)+ calcd 297.7; found: 298.1.
2-(2-Bromo-4-fluorophenylamino)-3-chloronaphthalene-1,4-dione
2-Chloro-3-(4-methoxyphenylamino)naphthalene-1,4-dione (1c).
1H NMR (DMSO-d6) d 9.22 (s, 1H), 8.03 (d, 2H, J = 6.3 Hz), 8.01
(m, 2H), 7.10 (d, 2H, J = 7.2 Hz), 6.90 (d, 2H, J = 8.7 Hz), 3.76
(s, 3H). LC-MS m/z (M + H)+ calcd 313.7; found: 314.1 and 315.2.
(2d). 1H NMR (DMSO-d6) d 9.18 (s, 1H), 8.04 (d, 2H, J = 9 Hz), 7.89
(m, 2H), 7.65 (d, 1H, J = 6.4 Hz), 7.45 (m, 1H), 7.26 (m, 1H). 13
C
NMR (75 MHz, DMSO-d6) d 180.09, 176.55, 149.09, 143.16,
136.11, 134.79, 133.78, 133.09, 131.95, 130.12, 128.38, 126.47,
126.02, 124.09, 113.29. LC-MS m/z (M À H)À calcd 378.9;
found: 378.0.
2-Chloro-3-(4-fluorophenylamino)naphthalene-1,4-dione (1d).
1H NMR (DMSO-d6) d 9.30 (s, 1H), 8.04 (d, 2H, J = 7.5 Hz),
7.89 (m, 2H), 7.18 (t, 4H, J = 5.4 Hz). 13C NMR (DMSO-d6)
d 179.97, 176.62, 160.13, 158.21, 143.33, 135.19, 134.74, 133.12,
131.90, 130.18, 126.46, 126.07, 126.01, 114.65, 114.47, 113.68.
LC-MS m/z (M + H)+ calcd 301.7; found: 300.1.
2-(2-Bromo-4-chlorophenylamino)-3-chloronaphthalene-1,4-dione
1
(2e). H NMR (DMSO-d6) d 9.17 (s, 1H), 8.04 (d, 2H, J = 9.0 Hz),
7.85 (m, 3H), 7.49 (t, 1H, J = 6.0 Hz), 7.39 (d, 1H, J = 7.5 Hz). 13
C
NMR (75 MHz, DMSO-d6) d 180.44, 177.46, 141.21, 137.64,
135.00, 134.72, 133.50, 131.65, 130.59, 129.96, 128.46, 128.03,
121.87, 118.26, 112.67. LC-MS m/z (M + H)+ calcd 394.3;
found: 395.9.
2-Chloro-3-(4-chlorophenylamino)naphthalene-1,4-dione (1e).
1H NMR (DMSO-d6) d 9.36 (s, 1H), 8.05 (d, 2H, J = 7.5 Hz),
7.90 (m, 2H), 7.37 (d, 2H, J = 8.7 Hz), 7.15 (d, 2H, J = 8.4 Hz).
LC-MS m/z (M + H)+ calcd 318.1; found: 320.0.
CT assisted nitration of 2-arylamino-3-chloro-1,4-naptho-
quinones (1a–e). To a vigorously stirred solution of the corre-
sponding 2-phenylamino-3-chloro-1,4-napthoquinone (1.000 mmol)
in acetonitrile, hexamethylbenzene (1.000 mmol) was added under
a nitrogen atmosphere at room temperature and stirred for 30 min
to form a CT adduct. Then NO2BF4 (1.200 mmol) was added to the
CT adduct solution. The resulting reaction mixture was stirred for
30 min to 1 h. The reaction mixture was monitored by TLC and after
completion of the reaction; the reaction mixture was washed with
sodium bicarbonate and water. The combined organic layer was
dried over anhydrous sodium sulfate, filtered and evaporated to
yield the product which was purified by column chromatographic
purification to get the pure product (yield 91–96%). These
compounds were characterized by various spectral techniques such
as 1H NMR, LC-MS, 13C NMR (a representative case) and 1H NOSEY
(a representative case) and the results are:
CT assisted bromination of 2-arylamino-3-chloro-1,4-napthoqui-
nones (1a–e). The suspension of the corresponding 2-arylamino-3-
chloro-1,4-napthoquinone (1.000 mmol) and hexamethylbenzene
(1.000 mmol) in dry CHCl3 (10 mL) under a nitrogen atmosphere
at room temperature was stirred vigorously for 30 min to form a CT
complex. Then Br2 (1.200 mmol) was added to the CT adduct
solution. The resulting reaction mixture was stirred for 30 min to
1 h. The reaction mixture was monitored by thin layer chromato-
graphy (TLC). After completion of the reaction; the reaction mixture
was washed with sodium bicarbonate and water. The combined
organic layer was dried over anhydrous sodium sulfate, filtered and
evaporated to yield the bromo derivative (2a–e) which was purified
using a 100–200 mesh flash column by using 30% of ethyl acetate in
petroleum ether to get the pure product as a yellow solid (72–97%).
The products were characterized using various spectral techniques
and the results obtained are given below.
2-(4-Nitrophenylamino)-3-chloronaphthalene-1,4-dione
(3a).
1H NMR (300 MHz, DMSO-d6) d 9.80 (s, 1H), 8.18 (t, 2H, J =
7.5 Hz), 8.09 (m, 2H), 7.93 (m, 2H), 7.25 (t, 2H, J = 7.5 Hz). 13C
NMR (75 MHz, DMSO-d6) d 180.24, 177.66, 146.61, 142.75,
142.19, 135.17, 134.21, 132.11, 131.11, 127.10, 126.17, 124.52,
122.26, 121.61. LC-MS m/z (M + H)+ calcd 328.7, found 329.1.
2-Chloro-3-(2,4-dibromophenylamino)naphthalene-1,4-dione (2a).
1H NMR (300 MHz, DMSO-d6) d 9.14 (s, 1H), 8.04 (d, 2H,
J = 6.9 Hz), 7.91 (m, 3H), 7.61 (d, 1H, J = 8.4 Hz), 7.33
(t, 1H, J = 6.9 Hz). 1H–1H COSY (DMSO-d6) correlation between
R2–H(d 7.30) and R3–H(d 7.61). 13C NMR (75 MHz, DMSO-d6)
d 179.30, 176.51, 143.51, 137.88, 134.95, 134.02, 133.34, 131.65,
130.59, 129.96, 129.90, 126.56, 126.11, 121.87, 119.00, 113.65.
LC-MS m/z (M + H)+ calcd 441.5; found 441.8.
2-(4-Methyl-2-nitrophenylamino)-3-chloronaphthalene-1,4-
1
dione (3b). H NMR (300 MHz, DMSO-d6) d 9.35 (s, 1H), 8.06
(m, 2H), 7.92 (s, 1H), 7.89 (m, 2H), 7.54 (d, 1H, J = 8.4 Hz), 7.29
2-Chloro-3-(2,6-dibromo-4-methylphenylamino)naphthalene-1,4- (d, 1H, J = 8.1 Hz), 2.40 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
dione (2b). 1H NMR (300 MHz, DMSO-d6) d 9.37 (s, 1H), 8.04 d 179.51, 176.66, 142.61, 141.69, 135.36, 134.93, 134.35, 133.51,
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NJC
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131.68, 131.19, 130.07, 127.35, 126.59, 126.22, 124.85, 116.34,
20.02. LC-MS m/z (M + H)+ calcd 342.7, found 343.1, 345.0
and 346.1.
2-(4-Methoxy-2-nitrophenylamino)-3-chloronaphthalene-1,4-dione
(3c). 1H NMR (300 MHz, DMSO-d6) d 9.26 (s, 1H), 8.05 (d, 2H, J =
5.7 Hz), 7.88 (t, 2H, J = 10.8 Hz), 7.59 (s, 1H), 7.40 (m, 2H), 3.87
(s, 3H). 13C NMR (75 MHz, DMSO-d6) d 180.02, 177.04, 157.16,
144.09, 143.55, 135.47, 133.87, 132.22, 130.47, 130.30, 127.08,
126.87, 126.66, 120.58, 114.83, 109.31, 56.57. LC-MS m/z (M + H)+
calcd 358.7, found 359.1, 361.0 and 362.0.
2-(4-Fluoro-2-nitrophenylamino)-3-chloronaphthalene-1,4-dione
1
(3d). H NMR (300 MHz, DMSO-d6) d (ppm) 9.34 (s, 1H), 8.04
(m, 3H), 7.92 (m, 2H), 7.69 (m, 1H), 7.52 (m, 1H). 13C NMR
(75 MHz, DMSO-d6) d 180.57, 177.74, 159.04, 146.16, 143.22,
135.20, 133.79, 132.20, 130.55, 130.38, 127.70, 127.64, 123.39,
115.03, 111.01. LC-MS m/z (M À H)À calcd 346.7, found 345.0.
2-(4-Chloro-2-nitrophenylamino)-3-chloronaphthalene-1,4-dione
1
(3e). H NMR (300 MHz, DMSO-d6) d 9.39 (s, 1H), 8.18 (d, 1H,
J = 1.8 Hz), 8.07 (t, 2H, J = 8.7 Hz), 7.92 (m, 3H), 7.43 (d, 2H,
J = 8.7 Hz). 13C NMR (75 MHz, DMSO-d6) d 180.21, 178.06,
153.86, 144.24, 141.15, 135.21, 133.52, 132.01, 131.78, 129.45,
126.82, 126.24, 123.40, 111.58. LC-MS m/z (M + H)À calcd 363.1,
found 361.0.
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Acknowledgements
The authors thank Ms S. Padmavathy, Assistant Professor,
Department of Zoology & Microbiology, Thiagarajar College,
Madurai 625009 for carrying out the biological activity of the
compounds. The authors also thank Dr S. Abraham John,
Associate Professor, Department of Chemistry, Gandhigram
Rural Institute, Gandhigram for providing electrochemical
workstation.
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