On-water reactivity and regioselectivity of quinones in C-N coupling with amines: Experimental and theoretical study

Article abstract of DOI:10.1071/CH13355

A study about the oxidative coupling of some representative carbo-and heterocyclic non-symmetrical quinones with aryl-and alkylamines, was carried out comparing dichloromethane and water as reaction mediums. We found that the on-water reactions gave better or, at worst, the same results as a conventional organic medium like dichloromethane. Descriptors derived from conceptual density functional theory and approaches of electrostatic nature, such as the molecular electrostatic potential, were used to explain the observed chemical reactivity and regioselectivity. Further, the on-water conditions were used to obtain 24 new aminoquinones with potential biological activity.

Full text of DOI:10.1071/CH13355

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH13355
On-Water Reactivity and Regioselectivity
of Quinones in C N Coupling with Amines:
]
Experimental and Theoretical Study
A C
,
A
Maximiliano Mart´ınez-Cifuentes,
Graciela Clavijo-Allancan,
A
B
Carolina Di Vaggio-Conejeros, Boris Weiss-Lo´pez,
A C
,
and Ramiro Araya-Maturana
A
Departamento de Qu´ımica Orga´nica y Fisicoqu´ımica, Facultad de Ciencias Qu´ımicas
Y Farmace´uticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
Departamento de Qu´ımica, Facultad de Ciencias, Universidad de Chile,
Casilla 653, Santiago, Chile.
B
C
Corresponding authors. Email: mmartinez@ug.uchile.cl; raraya@ciq.uchile.cl
A study about the oxidative coupling of some representative carbo- and heterocyclic non-symmetrical quinones with aryl-
and alkylamines, was carried out comparing dichloromethane and water as reaction mediums. We found that the on-water
reactions gave better or, at worst, the same results as a conventional organic medium like dichloromethane. Descriptors
derived from conceptual density functional theory and approaches of electrostatic nature, such as the molecular
electrostatic potential, were used to explain the observed chemical reactivity and regioselectivity. Further, the on-water
conditions were used to obtain 24 new aminoquinones with potential biological activity.
Manuscript received: 6 July 2013.
Manuscript accepted: 10 September 2013.
Published online: 11 October 2013.
Introduction
In this paper we report on the reactions between 1,4-quinone
derivatives: 2-methyl-1,4-benzoquinone I, 8,8-dimethyl-
naphthalene-l,4,5(8H)-trione II, 1,3-dimethyl-5,8-dioxo-5,8-
dihydroisoquinoline-4-carboxylic acid methyl ester III (used
as quinone-model compounds), with N-phenylpiperazine IVa
and aniline Va (used as amine-model compounds). Additionally,
several derivatives of IVa and Va with different substituents
were investigated to measure the scope of this reaction (Fig. 1).
Quinones I and II have been used before to obtain bioactive
natural and synthetics products.[25,26] Also, isoquinoline qui-
none III has been used as a substrate in oxidative coupling
reactions with amines to produce anti-tumour quinones.[27]
The two goals of this work were: first, to contribute to the
understanding of how water affects the reactivity and selec-
tivity of quinones in C–N coupling reactions with amines, and
second, to study a non-catalytic eco-friendly methodology, for
the regioselective oxidative coupling reaction of amines with
quinones. The results are explained using DFT calculations.
Global and local reactivity indexes and molecular electrostatic
potential (MEP) are used to discuss the changes in reactivity and
regioselectivity observed experimentally.
Quinone derivatives are considered a privileged skeleton in
medicinal chemistry as anticancer,[1] antifungal,[2,3] and anti-
parasitic[4] drugs. Quinones also have relevance in industrial
applications such as dyes,[5] and in the biodegradation of priority
pollutants.[6] Among quinones, aminoquinone derivatives are
remarkable, based on the potential biological applications
they posses. The aminoquinone motif[7] is a component of the
molecular framework of numerous natural products, such as
kinamycins,[8] caulibugulones,[9] griffithazanone A,[10] cyclos-
menospongine,[11] and others, and they have been used as
reactive intermediates for the synthesis of many biologically
relevant compounds.[12,13]
The synthesis of aminoquinones has been achieved, mainly,
through oxidative coupling of amines with quinones.[14] Signif-
icant attention has been devoted to improve the efficiency of this
reaction using Lewis acids like Ce(III),[15] Cu(II),[16] or Au(III)[17]
salts. Nevertheless, the use of heavy metals and volatile organic
compounds (VOCs) as solvents present serious environmental
impact, and reducing their use is a central issue in green
chemistry.[18] In view of the latter, new methodologies without
catalysts, using water as reaction medium have been developed
in recent years.[19,20] In addition to its positive environmental
properties, water presents unique reactivity and selectivity that
cannot be achieved by conventional organic solvents.[21,22]
On the other hand, several descriptors derived from con-
ceptual density functional theory (DFT)[23] and approaches of
pure electrostatic nature, such as molecular electrostatic poten-
tials,[24] have been used to assess chemical reactivity.
Theoretical Background
The energy gap between the highest occupied molecular orbital
(HOMO) and the lowest unoccupied molecular orbital (LUMO)
is indicative of the chemical reactivity of a molecule. Using
Koopman’s theorem for closed-shell compounds, the hardness,
Z, and the electronic chemical potential, m, can be defined as
Z ¼ (I –A)/2 and m ¼ –(IþA)/2, where I and A are the ionization
Journal compilation Ó CSIRO 2013
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B
M. Mart´ınez-Cifuentes et al.
2ðI ꢀ AÞ
O
O
N
NIII
¼
ð3Þ
ð4Þ
O
O
O
O
O
O
I2
5
4
II
1
2
1
2
10
12
1
2
4
16ðI ꢀ AÞ
NIV
¼
O
2
ð3I ꢀ AÞ
I
III
where the ionization potential (I) was approximated to EHOMO
and the electroaffinity (A) was approximated to ELUMO
.
H
H2N
N
On the other hand, the molecular electrostatic potential
(MEP) is related to the electron density and also is a very useful
descriptor of reactivity for electrophilicity and nucleophi-
licity.[35,36] To visualize the reactive sites of the studied qui-
nones, we calculated their MEP.
The efficiency of functionals employing different basis sets,
in predicting electronic properties including reactivity indexes
of some organic molecules has been systematically evaluated.
There being no significant change between the different levels
of theory,[37] our calculations were carried out at the B3LYP/
6–31G(d,p) level of theory.
R2
X
N
R1
Va-r
IVa-h
Va R2 ꢀ H
R
R
R
R
R
R
R
R
1 ꢀ H
IVa X ꢀ C
IVb X ꢀ C
Vb R2 ꢀ p-CH3
Vc R2 ꢀ o-CH3
Vd R2 ꢀ p-Cl
Ve R2 ꢀ m-Cl
Vf R2 ꢀ o-Cl
1 ꢀ o-OCH3
1 ꢀ m-OCH3
1 ꢀ o-F
1 ꢀ p-F
1 ꢀ p-NO2
1 ꢀ H
X ꢀ C
X ꢀ C
X ꢀ C
X ꢀ C
X ꢀ N
X ꢀ C
IVc
IVd
IVe
IVf
IVg
IVh
R2 ꢀ o-Br
R2 ꢀ p-Br
R2 ꢀ 3,4-diCl
R2 ꢀ p-OCH3
R2 ꢀ 3,4-diOCH3
R2 ꢀ p-COCH3
R2 ꢀ o-COCH3
R2 ꢀ p-CO2CH2CH3
R2 ꢀ o-CO2CH2CH3
R2 ꢀ p-F
Vg
Vh
Vi
Vj
Vk
Vl
Vm
Vn
Vo
Vp
Vr
1 ꢀ 3,4-diCl
Results and Discussion
The addition of aniline to quinone I, through an in-water, on-
water domino process starting from toluhydroquinone has
been reported. In this work, only the mono-addition product was
obtained.[38] In contrast, the products obtained from the reaction
of quinone I and p-benzoquinone with a series of anilines in the
two previous methods were only bis-addition products.[39] Thus,
we carried out the reaction of quinone I and II with aniline (Va)
and additionally tested the reaction with 1-phenylpiperazine
(IVa), commonly found within molecules with biological
activities.[40]
The reaction between I and IVa in equimolar ratio, using
dichloromethane as solvent, yielded two regioisomers, VI and
VII in 60 : 40 ratio, and 67 % yield. A modification of the
reaction conditions, using water as reaction milieu, changes
the results only slightly, obtaining a 55 : 45 ratio and 66 % yield.
Surprisingly, when aniline was used as nucleophile in dichlor-
omethane no reaction was observed, but when water was used as
solvent, three products were obtained X,VIII, and XI, in a ratio
of 70 : 20 : 10 and 87 % overall yield, taking into account that
50 % of the starting quinone acts as an oxidant of the amine
hydroquinone intermediates of the reaction. Considering a
stepwise reaction for the formation of the bis addition products,
we can postulate a regioselectivity of near 90 % for the first
addition (Scheme 1; Tables 1 and 2).
When 8,8-dimethyl-8H-naphthalen-1,4,5-trione II, a more
electrophilic quinone, reacts with both amines, a different
behaviour is observed. The reaction of quinone II with phenyl-
piperazine in dichloromethane as solvent generates only the
single regioisomer XII in 73 % yield. When the reaction is
carried out on-water the regioselectivity remains unaltered,
and the yield decreases slightly. Using aniline a rather different
behaviour is observed; when dichloromethane is used as solvent
a mixture of regioisomers XIV and XV is obtained, in ratio
70 : 30 and 40 % total yield, lower compared with that obtained
with phenylpiperazine (Scheme 2; Tables 3 and 4) .
On the other hand, the totally regio-controlled reactions of
III with aniline derivatives have been reported using
CeCl3 ꢁ 7H2O in ethanol at room temperature, to give an ami-
noquinone with anti-tumor activity.[27] To test for this reaction
in water, we chose some previously used aniline derivatives.
The products of this reaction were also obtained with a totally
regiocontrolled outcome. Although with slightly lower yields,
R2 ꢀ p-OH
Fig. 1. Compounds studied in this work.
potential and electron affinity respectively. Parr et al.[28] have
defined a descriptor to quantify the global electrophilic power as
an electrophilicity index (v): v ¼ m2/2Z.
Global reactivity indexes such as m and Z have been
approximated in terms of the one electron energies of the
frontier molecular orbitals HOMO and LUMO, eH and eL, using
the expression m E (eHþeL)/2 and Z E (eL–eH), from the
ground state of the molecules.[29] The local electrophilicity,[30]
vk, condensed to atom k, was obtained by projecting the global
quantity onto the atomic centre k in the molecule, by using the
condensed electrophilic Fukui function,[31] fkþ according to
vk ¼ v fkþ.
In addition to the electrophilicity index, several other
approaches have been proposed for the quantitative assessment
of nucleophilicity. Since electrophilicity and nucleophilicity are
inversely proportional, it has been suggested that nucleophilici-
ty, N, can be considered as the multiplicative inverse of the
electrophilicity index (Eqn 1).[32] Recently, new equations have
been proposed for nucleophilicity. One of them uses the HOMO
energy of the nucleophile and calculates the difference with
respect to the HOMO of tetracyanoethylene (TCE) (Eqn 2). TCE
is used as reference because it presents the lowest HOMO
among a great number of molecules.[33] Other methods to
calculate the nucleophilicity based on the electrodonating power
concept (v-)[34] have defined the nucleophilicity as the inverse
of electrodonating power (v-) and they have proposed two
equations to calculate it (Eqns 3 and 4), describing the latter
as the best[34b]
:
1
NI ¼
ð1Þ
ð2Þ
o
NII ¼ EH ðnuÞ ꢀ EH ðTCEÞ

On-Water Reactivity of Quinones Coupling with Amines
C
O
Ph
O
O
N
N
ꢁ
N
N
O
Ph
O
VI
VII
O
I
O
O
O
O
Ph
HN
O
Ph
HN
O
ꢁ
ꢁ
ꢁ
HN
Ph
NH
Ph
HN
Ph
NH
Ph
O
O
VIII
XI
IX
X
Scheme 1.
Table 1. Results for the reaction of quinone II with amine IVa
The global and local electrophilicities of quinone I and the
corresponding water complexes are presented in Table 6. We
found that global electrophilicity of this quinone (v ¼ 3.67)
increased their value remarkably when solvated with water
(v ¼ 4.36), which explains the differences observed when the
reaction with aniline was carried out on-water instead of
dichloromethane. In both cases, solvated or not with water,
local electrophilicity showed the same correlation, with C(2)
being the most electrophilic carbon (vk ¼ 0.40 not solvated, and
vk ¼ 0.47 solvated) and C(4) being the least (vk ¼ 0.30 not
solvated, and vk ¼ 0.32 solvated). This result is in agreement
with the experimental products ratio (Chart 1).
Solvent
%VI
%VII
% Overall yield
Dichloromethane
Water
60
40
55
45
67
66
Table 2. Results for the reaction of quinone II with amine Va
Solvent
%VIII
%IX
%X
%XI
% Overall yield
Dichloromethane
Water
0
0
0
0
0
0
20
70
10
87
Since the reaction of quinone I with aniline gave a second
addition product, we also calculated the properties of the mono
addition product and its water complexes. First, the potential
energy surface along dihedrals a and b were carried out for
molecules VIII and IX. The minimum energy conformations of
both molecules are presented in Fig. 2.
We found that water solvation also increased the reactivity of
mono addition products. The calculated local electrophilicity of
both VIII and IX showed that position 4 was largely more
reactive than 1 and 2, which explains why only X and XI were
obtained as products (Chart 2; Table 7).
The interaction of water molecules with quinone II has been
considered in two different coordination modes: two water
molecules, one with carbonyls 1 and 2, and the other with
carbonyl 3 (mode a, Chart 3), or three water molecules, one at
each carbonyl group, 1, 2, and 3 (mode b). Depending on the
coordination mode with water, the global electrophilicity
showed different behaviour. Unsolvated quinone shows a global
electrophilicity of 4.43 (Table 8).
Local electrophilicity showed that C(1) (vk ¼ 0.45) is more
reactive than C(2) (vk ¼ 0.30), which agrees with the experi-
mental regioselectivity in dichloromethane. C(4) and C(5) also
have a high electrophilicity; nevertheless it has been proposed
that the gem-dimethyl group generates a steric effect which
blocks the reactivity of these carbons for Diels–Alder reac-
tions.[42] This is in accordance with the results for oxidative
addition reactions.
this simple change of conditions ensured products free of
potentially toxic metals, such as cerium(III) (Scheme 3; Table 5).
Analysis of Global and Local Properties
We calculated the global and local electrophilicities of quinones
I, II, III, IX, and X, and the global nucleophilicity of amines
IVa and Va. Also, to study solvation effects in the reactivity of
these molecules, we calculated their complexes with water
molecules. Different methodologies have been used to include
water solvation in theoretical studies of reactivity, either in
implicit and/or explicit forms. Recently, five different methods
to study the inclusion of solvent effects on reactivity properties
have been reported: 1) polarizable continuum model (PCM),
an implicit form; 2) using 499 point charges (PC), an explicit
form, 3) using 2 explicit water molecules and 497 point
charges representing the same number of water molecules, 4)
40 explicit water molecules and 459 point charges, and 5)
2 explicit water molecules in vacuum; it was found that only the
continuum model (PCM) was incapable of obtaining a signif-
icant change in the energies of the HOMO and LUMO orbitals,
with respect to the values obtained in gas phase. Furthermore,
the differences in the values of the reactivity indexes among the
explicit methodologies are minimal. Therefore, the coordina-
tion of each basic centre in a studied molecule with a water
molecule in vacuum is a reasonable choice to obtain reliable
results for reactivity indexes.[41]
In coordination mode a, the global electrophilicity of the
solvated quinone was slightly reduced, from 4.43 to 4.33, and

D
M. Mart´ınez-Cifuentes et al.
O
O
O
O
N
N
N
ꢁ
O
N
O
XII
XIII
O
O
O
II
O
O
O
O
O
O
H
N
ꢁ
N
H
XIV
XV
Scheme 2.
Table 6. Global and local electrophilicities of
quinone I and their water complexes Ia
Table 3. Results for the reaction of quinone II with amine IVa
Solvent
%XII
%XIII
% Overall yield
Compound
v
Site
vk
Dichloromethane
Water
100
100
0
0
73
70
I
3.67
1
2
4
1
2
4
0.36
0.40
0.30
0.43
0.47
0.32
Ia
4.36
Table 4. Results for the reaction of quinone II with amine Va
Solvent
%XIV
%XV
% Overall yield
%XIV
H
Dichloromethane
Water
70
30
0
40
88
70
O
H
100
100
O
O
H
N
O
O
1
2
1
2
H2O
N
N
R
4
4
Aniline
derivatives
O
O
H
O
CO2Me
O
CO2Me
I
Ia
O
H
III
Scheme 3.
Chart 1.
Table 5. Results for the reaction of quinone III with aniline derivatives
β
α
Compound
R
Yield [%]
α
β
XVI
-H
61
63
54
67
XVII
XVIII
XIX
-p-Methoxy
-p-Fluoro
-p-Hydroxy
VIII
IX
Fig. 2. Optimized geometry of mono-addition products of aniline and
quinone (I).
the local electrophilicity on C(1) and C(2) showed a larger
difference (0.44 vs 0.22) than in the non-solvated case (0.45 vs
0.30). On the other hand, in coordination mode b, the global
electrophilicity increased their value from 4.43 to 4.87, and the
local electrophilicity difference of C(1) and C(2) remains the
same, 0.51 and 0.36. The results from coordination mode a are in
agreement with the increase in the observed regioselectivity
when the reaction with aniline was performed in water instead
of dichloromethane. On the other hand, coordination mode

On-Water Reactivity of Quinones Coupling with Amines
E
H
O
H
O
O
H
H
O
O
O
O
H
H
N
1
N
1
4
4
2
4
N
N
H
2
4
O
O
H
H
O
H
IXa
IX
VIIIa
VIII
H
O
O
H
Chart 2.
H
O
Table 7. Results of mono-addition products, electrophilicities of ani-
line on quinone I, and their water complexes
H
O
O
N
O
O
N
O
O
O
VIII
Site vk
VIIIa
Site vk
IX
Site vk
IXa
Site vk
1
1
2
2
v 3.52
1
4
0.14 v 4.07
0.23
1
4
0.12 v 3.61
0.23
2
4
0.17 v 4.30
0.50
2
4
0.15
0.60
O
H
lll
llla
O
H
H
H
O
O
H
O
H
O
H
O
H
Chart 4.
O
O
O
O
5
5
4
5
4
1
2
1
2
10
12
1
2
Table 9. Global and local electrophilicities
of quinone III and their water complexes IIIa
10
12
10
12
4
O
H
O
O
Compound
v
Site (k)
vk
llb
H
II
III
3.78
1
2
1
2
0.37
0.48
0.40
0.52
IIa
O
O
H
H
IIIa
4.33
Chart 3.
Table 8. Electrophilicties of quinone II and their water complexes
II IIa IIb
Site Site Site
Table 10. Nucleophilicity of amines IVa, Va and
their water complexes
Method
IVa
IVa1
Va
Va1
vk
vk
vk
1
2
4
5
0.45
0.30
0.49
0.44
1
2
4
5
0.44
0.22
0.46
0.48
1
2
4
5
0.51
0.36
0.47
0.46
1
2
3
4
3.73
1.74
3.56
3.07
3.18
1.27
3.44
3.10
3.90
1.43
3.68
3.15
3.78
1.61
3.65
3.20
v
4.43
v
4.33
v
4.87
10 0.01
12 0.02
10 0.01
12 0.03
10 0.02
12 0.02
mentioned in the theoretical background section (Table 10).
From this data we observe that only method 2 reproduces
correctly the reactivity increase of aniline IV when solvated with
water; it also predicts correctly that phenylpiperazine V is more
reactive thananilineIVwithoutthe watersolvation, whichagrees
with the experimental behaviour observed in dichloromethane.
b correctly predicts the reactivity increase when the reaction was
performed in water. The coordination energies of modes a and b
are very similar (DE ¼ 0.12 kcal molꢀ1; 1 kcal molꢀ1 ¼ 4.186 kJ
molꢀ1); in this way, both modes contribute to explain the
observed increase in reactivity and regioselectivity (Chart 3).
Reactivity indices of isoquinoline quinone III and the
complex with two water molecules were also calculated. We
found that water solvation increases the electrophilicity of
the molecule from 3.78 to 4.33. The local electrophilicity
difference between carbon 8 and 10 also increase slightly. These
results are in agreement with the experimental observations,
which showed that the effect of water was almost equivalent to
use of Ce(III) salts as catalyst in ethanol, as previously reported
(Chart 4; Table 9).[27]
Molecular Electrostatic Potential
To generate the MEP the colour-coded values were projected
onto the 0.02 a.u. iso-potential energy surface. The red colour
indicates negative sites of the molecule, showing possible
positions for electrophilic attack, while the blue colour indicates
positive sites, potentially suitable for nucleophilic attacks. We
calculated MEP for quinones I, II, III, VIII, IX and their water
complexes. As expected, quinone I showed two electron-rich
sites on the oxygens and three electron-deficient sites on C(1),
C(2), and C(4). The MEP of complex Ia showed that C(1) and
We also calculated the nucleophilicity of amines IVa and Va
and their water complexes IVa1 and Va1, through methods 1 to 4

F
M. Mart´ınez-Cifuentes et al.
Ia
I
VIII
VIIIa
IXa
IX
Fig. 3. MEP of quinone (I), the mono-addition products with aniline, and the water complexes.
IIb
II
IIa
Fig. 4. MEP of quinone II and their water complexes.
C(2) increased their electron-deficient character, while in C(4) it
almost disappears. The MEP of aminoquinones IX and X
and their water complexes showed that C(4) is more electron-
deficient than C(1), which is in agreement with the local elec-
trophilicities calculated before and also with the experimental
results (Fig. 3).
III
IIIa
Quinone II showed three electron-rich sites on the carbonyl
oxygen atoms. The two neighbouring carbonyl oxygens gener-
ate a strong negative region around that side of the molecule.
On the other hand, the carbonyl oxygen closest to the gem-
dimethyl group exhibited a less electron-rich site; besides it is
distorted due to steric effects of the gem-dimethyl moiety. This
molecule also showed electron-deficient sites on C(1) and C(2).
Complex IIa showed that the electron density of the water
molecule coordinated to oxygen at the carbonyl between C(2)
and C(4) is blocking C(2). This stereo-electronic hindrance,
along with the variation of the local electrophilicity in C(1) and
C(2), can explain the increase in regioselectivity of the reaction
with aniline. The complex IIb showed an electron density
distribution similar to II(Fig. 4).
Isoquinoline quinone III exhibited four electron-deficient
sites, localized on two carbonyl carbons, C(1) and C(2), being
these last positions where oxidative addition can occur.
The water complex, IIIa, showed an increase in the electron-
deficient character of C(1), but it disappears from C(2) due to
the hindrance induced by coordination of water with the neigh-
bouring carbonyl. These results showed that both the local
reactivity difference and the stereo-electronic effects are
Fig. 5. MEP of quinone III and their water complexes.
involved in the high regioselectivity at C(1) displayed by the
reaction (Fig. 5).
Use of On-Water Methodology to Obtain Substituted
Aminoquinones Derived from Quinone II
Quinone II was used as a scaffold to produce biologically
active compounds. Because of the remarkable results, the on-
water conditions were used to produce a series of aniline and
N-phenylpiperazine derivatives. In order to evaluate the effect
of the electronic nature of the substituents on the reactivity and
regioselectivity of these reactions, they were carried out with a
series of substituted amines (Chart 5; Table 11).

On-Water Reactivity of Quinones Coupling with Amines
G
X
only give results similar to conventional ones but also improved
yields and selectivities.
R
O
O
O
N
O
O
O
H
N
N
Synthetic General Procedure
R
The reaction of quinone I with amine IVa was carried out
using condition B. The reactions of quinones I and II with
amines IVa and Va were carried out using conditions A and B,
both described below. The reactions of quinone II with amines
IVb to IVg and Vb to Vn were carried out using conditions B. The
synthesis of compounds II,[43] VIII-IX, XI,[44] and XVI-
XIX[27] have been previously described.
Chart 5.
Table 11. Yields of substituted aminoquinones derived from quinone
II, obtained in water
A) Dissolving reactants in dichloromethane and stirring at
room temperature overnight.
B) Using water as the reaction medium and stirring at room
temperature overnight.
Compound
R1
Yield Compound
[%]
X
R2
Yield
[%]
XXa
XXb
p-CH3
o-CH3
68
81
XXIa
XXIb
C
C
o-OCH3
m-
68
81
OCH3
o-F
Computational Details
XXc
XXd
XXe
XXf
XXg
p-Cl
m-Cl
o-Cl
o-Br
p-Br
65
57
51
47
57
XXIc
XXId
XXIe
XXIf
XXIg
C
C
C
N
C
65
57
36
59
57
Calculations were carried out using DFT with the B3LYP
functional,[45,46] together with the standard 6–31G(d,p) basis
set. No imaginary frequencies were found at the optimized
molecular geometries, which indicate that they are real minima
of the potential energy surface. All calculations were carried out
using the Gaussian 03[47] program package, running in a
Microsystem cluster of blades. Calculations of global and local
DFT-defined chemical reactivity descriptors were carried out
using Fukui2 program.[48]
p-F
p-NO2
H
3,4-di-
Cl
XXh
XXi
XXj
XXk
XXl
XXm
3,4-di-Cl
p-OCH3
74
92
95
41
36
59
3,4-di-OCH3
p-COCH3
o-COCH3
p-
Supplementary Material
CO2CH2CH3
o-
1H-RMN, 13C-RMN, IR, HRMS data and melting points for new
compounds, as well as Cartesian coordinates and energies for
the optimized structure calculated are available on the Journal’s
website.
XXn
57
CO2CH2CH3
The results show that the on-water reaction tolerated the
different nature of the substituents on the aromatic ring of the
amine. Better yields are obtained with the stronger electron-
donor substituents, which increased the nucleophilicity of the
aromatic amines. However, strong electron-releasing groups
also gave the corresponding products, although with lower
yields. For phenylpiperazines, the substituent did not directly
affect the nucleophilicity of the nitrogen, but differences were
also detected with the modification of that substituent.
Acknowledgements
This work was supported by FONDECYT grant 1110176, and Anillo ACT-
1107. M.M-C thanks CONICYT for PhD fellowship No. 21090023 and Beca
Chile No. 75120034.
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