Experimental and theoretical investigation of the reaction of secondary amines with maleic anhydride

Article abstract of DOI:10.1071/CH17206

The reaction of secondary amines, namely 1-methylpiperazine, pyrrolidine, morpholine, 2-methylpiperidine, and diethylamine, with maleic anhydride has been investigated experimentally and theoretically at the DFT level. Under kinetic control, i.e. at -78°C

Full text of DOI:10.1071/CH17206

CSIRO PUBLISHING
Aust. J. Chem. 2017, 70, 1247–1253
Full Paper
https://doi.org/10.1071/CH17206
Experimental and Theoretical Investigation of the Reaction
of Secondary Amines with Maleic Anhydride
A
A
A B
,
Manjinder Kour, Raakhi Gupta, and Raj K. Bansal
A
Department of Chemistry, The IIS University, Jaipur 302020, India.
Corresponding author. Email: bansal56@gmail.com
B
The reaction of secondary amines, namely 1-methylpiperazine, pyrrolidine, morpholine, 2-methylpiperidine, and
diethylamine, with maleic anhydride has been investigated experimentally and theoretically at the DFT level. Under
kinetic control, i.e. at ꢀ788C or ꢀ158C, amines add across the C=O functionality exclusively and the initially formed
addition products isomerize to the corresponding N-substituted maleimic acid derivatives. In contrast to the acyclic
a,b-unsaturated carbonyl compounds, amine does not add across the C=C functionality in maleic anhydride even under
thermodynamic control. This behaviour of maleic anhydride can be rationalized on the basis of the local condensed Fukui
functions, which reveal that the carbonyl carbon atoms in maleic anhydride are much harder than in an acyclic
a,b-unsaturated carbonyl compound, such as acrolein. This prompts the amines to attack the carbonyl group in maleic
anhydride exclusively.
Manuscript received: 13 April 2017.
Manuscript accepted: 24 June 2017.
Published online: 20 July 2017.
Introduction
O
O
The chemistry of maleic anhydride continues to attract the
attention of chemists working in the fields of organic synthesis
and material sciences owing to the presence of several reactive
functionalities in this molecule.[1,2] A C=C functionality, acti-
vated by its conjugation with the carbonyl groups on both sides,
makes it a potent dienophile.[3,4] This may be expected to
undergo nucleophilic addition across the C=O functionality. In
fact, maleic anhydride has been reported to react with primary
amines to yield maleimic acids, which change to N-substituted
maleimides on heating in the presence of a dehydrating
agent.[5–8] However, only one report could be found about the
reaction of maleic anhydride with a secondary amine, namely
1-methylpiperazine, to give N-(1-methylpiperazin-4-yl)mal-
eimic acid, which does not cyclize in the absence of an NH
atom. However, no spectral data of this compound were given in
the paper.[9] The integration of an a,b-unsaturated carbonyl
functionality in a maleic anhydride molecule is expected to
make it a good Michael acceptor. Diphenylphosphine reacts
with maleic anhydride and its a-methyl derivative to afford the
corresponding Michael adducts (Scheme 1).[10] However, tri-
phenylphosphine[11,12] and triethyl phosphite,[13] which have no
hydrogen atoms on the donor P atom, react with maleic anhy-
dride to form ylide-type products 4 and 5, respectively,
involving nucleophilic attack at the a-alkenyl carbon atom
followed by the transfer of the proton to the adjacent carbon
atom (Scheme 1).
O
O
Ph2PH ϩ
Ph2P
O
O
O
1
2
3
5
O
O
O
ϩ
(C3H2O)3P
(C6H5)3P
OϪ
O
4
Scheme 1.
exists for the addition across the C=C bond or the C=O
functionality, and these types of additions have been named as
conjugate (1,4-) versus direct (1,2-) addition, respectively, in the
literature. However, in the present article, we have used the
terminology of additions across the C=C and C=O functionali-
ties (Scheme 2) in order to avoid confusion, such as 1,2- versus
1,4-addition of halogens to the conjugated dienes.
Schultz and co-workers[24] were the first to systematically
study the factors affecting addition of the stabilised enolates
derived from a-substituted methyl propiolates across the C=C
and C=O functionalities in 2-cyclohexen-1-one. They found that
addition across the C=O group is kinetically preferred and occurs
predominantly or exclusively at low temperature, i.e. at ꢀ788C,
whereas addition to the C=C moiety is, in general, thermody-
namicallyselective and the initially formedC=Oadditionproduct
on raising the temperature to 258C changes into the C=C addition
product. However, the reactionofthe enolate ion derived fromthe
Michael addition of nucleophiles to activated alkenes and
alkynes provides one of the most commonly used methods for
making C-C and C-X (X ¼ N, O, P, S) bonds in organic
synthesis.[14–23] However, in the reaction with a,b-unsaturated
carbonyl compounds, such as maleic anhydride, the possibility
Journal compilation Ó CSIRO 2017
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1248
M. Kour, R. Gupta and R. K. Bansal
O
H
O
O
O
R4
R3
H
H
R1
R2
CϭC Addition
R1R2NH
O
O
O
ϩ
O
H
R1
R2
Nu
NuH
7
R4
R1R2N
8
OH
NR1R2
11
O
O
R3
OH
R4
Nu
13
10
2
R1
CϭO Addition
6
R3
R2
9
O
Scheme 2.
OH
NR1R2
acetonide of lactic acid with 2-cyclohexen-1-one at ꢀ788C or
258C over a prolonged reaction time yielded only the C=O
addition product ruling out the reversibility of the reaction at
the latter reaction conditions. From these results, they concluded
that by simple structural modification and careful choice of
reaction temperature, it was possible to direct the reaction of
enolates to cyclohexenone either to the C=O or the C=C addition.
In a similar study, Reich et al.[25] investigated the role of the
solvent in the reaction of sulphur-substituted carbanionic lithium
reagents with 2-cyclohexen-1-one and concluded that under
contact ion pairs (CIP) conditions (in the presence of tetrahydro-
furan or diethyl ether), the C=O addition product is favoured
exclusively, whereas under solvent-separated ion pair (SIP)
conditions (in the presence of hexamethylphosphoramide),
C=C addition occurs predominantly.
O
12
Scheme 3.
local sense, one may establish the behaviour of different sites
with respect to hard or soft reagents’.[32]
It was demonstrated that most of the frontier-electron theory
of chemical reactivity can be well rationalized on the basis of
density functional theory (DFT) of the electronic structure of the
molecules.[36,37] Yang and Mortier[38] subsequently suggested
the use of the gross charge (qr) at a particular atom r in a
molecule obtained from Mulliken population analysis (MPA) to
determine the condensed Fukui function (fr) at that atom. Thus,
In contrast to the intensive kinetic studies of the reactions of
enolates with a,b-unsaturated carbonyl compounds, only one
report[26] could be found about these aspects of the reaction for
primary amines with a,b-unsaturated aldehydes and ketones
although the aza-Michael reaction has been extensively used
for obtaining important synthons, such as b-amino carbonyl
compounds and heterocyclic scaffolds.[27–31] Whiting and
co-workers[26] investigated the addition of primary amines to
a,b-unsaturated aldehydes and ketones (C=O versus C=C addi-
f þr ¼ qrðN þ 1Þ ꢀ qrðNÞ for nucleophilic attack
f ꢀr ¼ qrðNÞ ꢀ qrðN ꢀ 1Þ for electrophilic attack:
ð3Þ
ð4Þ
As discussed earlier, no attempt has been made so far to
investigate the reactions of secondary amines with maleic
anhydride under kinetic and thermodynamic controls. Further-
more, in contrast to the reaction with an acyclic a,b-unsaturated
carbonyl compound, in the present case, the possibility of an
equilibrium between three species (11, 12, 13) exists
(Scheme 3).
With this background, we investigated the reaction of some
secondary amines with maleic anhydride under kinetic and
thermodynamic controls and attempted to rationalize the
observed regioselectivity on the basis of the condensed Fukui
functions; the results are presented here.
1
tion) by using a combination of in situ IR, H NMR and DFT
calculations, and concluded that formation of the a,b-unsaturated
imines (through addition to the C=O group) is kinetically con-
trolled for all enols and most enones with the exception of methyl
vinyl ketone, which resulted in addition across the C=C function-
alityexclusively. Furthermore,DFTcalculationsindicatedthat the
selectivities are governed by conformational and stereo-electronic
effects.
Ga´zquez and Mendez[32] extended the concept of hard-soft
acid-base (HSAB) theory[33–35] to explain the global and local
reactivity of organic molecules towards nucleophilic and elec-
trophilic reagents. Thus, the chemical reactivity at a particular
molecular site could be rationalized by using a quantitative
descriptor, the Fukui function (e(r)), arising from finite differ-
ence approximation. Thus, the Fukui function was defined as
Results and Discussion
Experimental Results
We investigated the addition of five secondary amines (14) with
maleic anhydride under kinetic control, i.e. at low temperature
(ꢀ788C or ꢀ158C) and under thermodynamic control at higher
temperature (408C) (Scheme 4).
f þðrÞ ¼ rNþ1ðrÞ ꢀ rNðrÞ for nucleophilic attack ð1Þ
f ꢀðrÞ ¼ rNðrÞ ꢀ rNꢀ1ðrÞ for electrophilic attack: ð2Þ
In a typical experiment, to a cooled solution (ꢀ788C or
ꢀ158C) of maleic anhydride in methylene chloride, 1 equivalent
of amine was added and the reaction mixture was stirred at the
same temperature for 0.5 h followed by removal of the solvent
(at the same low temperature). In the case of the reaction at
higher temperature, after adding the amine to the solution of
maleic anhydride in methylene chloride, the reaction mixture
was refluxed for 1 h followed by distilling off the solvent. The
1H NMR spectra of the viscous mass so obtained were scanned
in CDCl3. These spectra are given in the Supplementary
Material.
where rNþ1(r), rN(r) and rNꢀ1(r) are the electron densities at
a point r in the system with Nþ1, N and Nꢀ1 electrons,
respectively, all with the ground state geometry of the N electron
system.
They concluded, ‘regions of a molecule where the Fukui
function is large are chemically softer than the regions where the
Fukui function is small and by invoking the HSAB principle in a

Reaction of Secondary Amines with Maleic Anhydride
1249
O
O
1
the relative percentages of the two products under different
conditions could not be determined.
The reaction with piperazine afforded a polymeric substance
which was found to be insoluble in common organic solvents but
soluble in water.
O
H
R1
2
H
H
OH
NR1R2
ϩ
NH
ϩ
O
4
O
R2
H
H 3
H
OH
O
R1R2N
O
It may be noted that, as expected, at low temperature (ꢀ788C
or ꢀ158C), addition across the C=O functionality occurs exclu-
sively or predominantly. On heating the reaction mixture at
408C, i.e. on refluxing in methylene chloride, the initially
produced major C=O addition products in the reactions with
14a, 14b and 14c change into the corresponding maleimic acids
to varying extents. Pure maleimic acid derivatives of these three
amines could be obtained by refluxing the reaction mixtures in
acetonitrile for ,2 h followed by column chromatography and
recrystallization from methanol. However, similar efforts to
obtain pure maleimic acid derivatives of 2-methylpiperidine and
diethylamine were not successful.
14a–e
2
15
16
a
b
c
d
e
1Ј 2Ј
NH , 3Ј
1Ј 2Ј
1Ј
5Ј
4Ј
2Ј
R1R2NH
NH
Me N
NH
O
NH
NH
HD
HE
,
,
,
2Ј
1Ј Me
Scheme 4.
Formation of the product 15, resulting from addition of
amine across the C=O group of maleic anhydride, could be
confirmed by the presence of two doublets in the H NMR
1
spectrum at d ,6 ppm with a 3JHH of ,12 Hz resulting from an
AB spin system constituted by two cis-vinylic protons. However,
the presence of two doublets slightly further downfield with a
3JHH of ,11–15 Hz indicates the formation of the maleimic acid
derivative 16.[8] The structure of a representative compound
16a, prepared in pure form as described later, was established
Theoretical Results
The values of the global hardness (Z) and global softness (s), and
the condensed Fukui functions eþr and eꢀr, and local softness
sþr and sꢀr at different atoms of maleic anhydride and at the
donor nitrogen atom (NH) of amines used in the reactions are
given in Tables 2 and 3, respectively.
unambiguously by the H-13C correlated 2D NMR spectrum
1
It may be noted that condensed Fukui functions of many
atoms, including those of the carbonyl carbon atoms in maleic
anhydride and donor nitrogen atoms in amines, have negative
values. The condensed Fukui functions with negative values
have been often obtained while using MPA.[40,41] However,
application of Hirshfeld population analysis (HPA),[42] based on
the stock-holder idea, yields only positive condensed Fukui
functions.[40,43] Later, negative condensed Fukui functions were
rationalized by invoking orbital relaxation effects. Thus, theo-
retical calculation of the redox-induced electron rearrangement
(RIER) revealed that although the molecule loses one electron,
the electron density may increase in some regions leading to the
negative condensed Fukui functions.[44,45] Ga´zquez and Men-
dez[32] also found negative values of the condensed Fukui
function at the carbonyl carbon atoms of the substrates used in
the reactions.
Unlike in simple a,b-unsaturated aldehydes or ketones, such
as acrolein (Fig. 2), the -CH=CH- functionality in maleic
anhydride (2) is encompassed by the carbonyl groups on both
sides. Thus, in contrast to acrolein, in the maleic anhydride
molecule, the C=O and C=C groups are locked in the s-trans
conformation and the value of the condensed Fukui function for
the nucleophilic attack (fþr) at the carbonyl carbon atom in
maleic anhydride (0.003) is much smaller than in acrolein
(0.215), which shows the much harder character of the former.
The b carbon atom (C3) in maleic anhydride is much softer
compared with the carbonyl carbon atom. This difference
(difference between the hardnesses of the carbonyl carbon atom
and b carbon atom) in acrolein is much smaller. From this, it
may be concluded that under kinetic control conditions, attack at
the carbonyl carbon atom in maleic anhydride leading to
addition across the C=O group will be much more preferred
than in acrolein under similar conditions.
(solvent: CD3OD, given in Supplementary Material), wherein
two proton signals at d 6.7 and d 6.9 ppm correlated with the 13C
NMR signals at d 130.9 and d 132.2 ppm, respectively, thereby
confirming the vinylic nature of the protons. These NMR data
rule out structure 13 for these products. We realise that in an
earlier communication,[39] structure 13 was erroneously
assigned to these products and this should be revised. Thus, in
contrast to the acyclic a,b-unsaturated carbonyl compounds, in
the present case, the initially formed product from the addition
of a secondary amine across the C=O functionality of maleic
anhydride isomerizes to N-substituted maleimic acid, rather
than changing back to the reactants, and then to the C=C addition
product under thermodynamic control, i.e. at higher tempera-
ture. The stabilisation of the maleimic acid derivative resulting
from delocalization of the nitrogen lone pair of the amidic
moiety appears to be responsible for the preferred formation
of these compounds. The relative percentages of the products 15
and 16 were calculated on the basis of the intensities of doublets
of the vinylic proton in 15 and 16 in the 1H NMR spectra. The 1H
NMR signals between d 6–8 ppm obtained from the products of
the reaction of 1-methylpiperazine with maleic anhydride under
different conditions are reproduced in Fig. 1.
It is noteworthy that the initially formed C=O addition
product of amine does not completely change to maleimic acid
even on heating the reaction mixture at 408C for 1 h. As the
removal of the solvent at ꢀ788C took a prohibitively long time,
except for the reaction with 1-methylpiperazine and pyrrolidine,
the reactions with the other amines were studied only at ꢀ158C
and 408C.
The percentages of the C=O addition products (15) and the
corresponding maleimic acids (16) determined on the basis of
the 1H NMR spectra, as outlined earlier, formed from the
reactions of amines with maleic anhydride under different
conditions are given in Table 1. It was found that the doublets
of the vinylic protons of the C=O addition product and those of
the maleimic acid derivative obtained from the reaction of
2-methylpiperidine with maleic anhydride overlap, and therefore
The LUMO and the electrostatic potential map of the maleic
anhydride molecule are shown in Fig. 3.
It may be noted that the LUMO of the maleic anhydride
molecule is composed of the p*C=O and p*Ca=Cb orbitals
merged together. In view of this, the attacking nucleophile has

1250
M. Kour, R. Gupta and R. K. Bansal
7.0
6.5
6.0
7.0
6.5
6.0 [ppm]
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 [ppm]
Ϫ78ЊC
Ϫ15ЊC
40ЊC
Fig. 1. Part of the 1H NMR spectra of the products formed from the reaction of 1-methylpiperazine with maleic anhydride at different temperatures.
Table 1. Relative percentages of the products 15 and 16 in the reactions of secondary amines with maleic anhydride (solvent:
methylene chloride)
Entry no.
Amine
1a
Temp [8C]
Relative percentage [%]
C=O Addition product 15
Maleimic acid derivative 16
1
ꢀ78
ꢀ15
40
90
77
30
72
11
–
10
23
70
28
89
100
5
2
3
4
1b
ꢀ78
ꢀ15
40
5
6
7
1c
1d
1e
ꢀ15
40
95
8
7
93
A
A
9
ꢀ15
40
–
–
A
–
A
10
11
12
–
ꢀ15
40
100
91
–
9
ARelative percentages could not be determined.
both opportunities, i.e. either to attack the carbonyl carbon
atom or the Cb atom of the C=C functionality. This preference
will, however, be determined by the relative condensed Fukui
functions for the nucleophilic attack (fþr) at these two sites as
well as the conditions. Amines are known to have intermediate
hardness and can attack either of the two sites depending upon
the conditions. Thus, under kinetic control, i.e. at low temper-
ature, the carbonyl carbon atom, which is the harder site
(fþr ¼ 0.003), is attacked giving the C=O addition product.
The preferential attack of amine on the carbonyl carbon atom
is in accordance with the electrostatic potential map which
also shows the highest electron deficiency (highest intensity of
blue colour) at this site.
It may be noted that lone pairs on the two nitrogen atoms
constitute the HOMO of 1-methylpiperazine. However, the lone
pair on the nitrogen atom of NH (N18 in Fig. 4a), being sterically
less hindered, attacks the maleic anhydride molecule. In the
electrostatic potential map, the intensity of the red colour also
indicates the high electron density on the nitrogen atom.
Conclusions
The reaction of secondary amines with maleic anhydride under
kinetic control conditions occurs across the carbonyl group
exclusively, which may be attributed to the much harder nature
of its carbonyl carbon atom as compared with that in an acyclic
a,b-unsaturated carbonyl compound, such as acrolein. It could be
rationalized theoretically on the basis of the condensed Fukui
function which reveals the hardest nature of the carbonyl carbon
atom making it the preferred site for the nucleophilic attack. The
The HOMO and the electrostatic potential map of a repre-
sentative amine, namely 1-methylpiperazine (14a), are given in
Fig. 4. The HOMOs and electrostatic potential maps of other
amines are provided in the Supplementary Material.

Reaction of Secondary Amines with Maleic Anhydride
1251
Table 2. Condensed Fukui functions e1r and e2r and local softness
(s1r and s2r) values at different atoms of the maleic anhydride molecule
calculated at the B3LYP/6–31111G**//B3LYP/6–311G* level
Experimental
Materials
Commercially available amines, maleic anhydride and
dichloromethane were purchased from Sigma-Aldrich.
Dichloromethane was freshly dried and distilled.
6
O
5
4
O
7
3
2
Analysis and Characterisation of Products
O
1
IR spectra were recorded on a Perkin Elmer FT-IR spectrometer.
NMR spectra were recorded on a Bruker-DPX-300 MHz spec-
trometer. 1H NMR were recorded at a frequency of 300.13 MHz
and 13C NMR at 75.48 MHz using tetramethylsilane (TMS) as
the internal reference. High resolution mass spectra (HRMS)
were recorded on a mass spectrometer, model Xevo G2-S Q Tof
(Waters, USA) with UPLC.
Global hardness η ϭ Ϫ0.272 and global softness s ϭ Ϫ1.836
Atom
eþx
sþx
eꢀx
sꢀx
O1
C2
C3
C4
C5
O6
O7
ꢀ0.069
ꢀ0.003
ꢀ0.045
ꢀ0.158
ꢀ0.003
ꢀ0.191
ꢀ0.191
0.127
0.006
0.083
0.290
0.006
0.351
0.351
ꢀ0.106
ꢀ0.012
ꢀ0.047
ꢀ0.085
0.012
0.195
ꢀ0.022
0.086
General Method
0.156
A solution of 2 (1g, 10.20mmol) indichloromethane(10 mL) was
cooled to ꢀ788C in a cryostat under anhydrous conditions. To it
was added dropwise a solution of 1 equiv. of amine (14a, 1.021 g,
1.13 mL, 10.20 mmol; 14b, 0.725 g, 0.83 mL, 10.20 mmol; 14c,
0.888 g, 0.89 mL, 10.20 mmol; 14d, 1.011 g, 1.19 mL,
10.20 mmol; 14e, 0.745 g, 1.05 mL, 10.20 mmol) in methylene
chloride (5mL) with continuous stirring and the temperature was
maintained at ꢀ788C. After the addition was complete, the reac-
tion mixture was stirred for another 0.5h at the same temperature.
The solvent was thereafter removed under vacuum with main-
taining the temperature at ꢀ788C. The viscous mass so obtained
ꢀ0.022
0.534
ꢀ0.291
ꢀ0.290
0.532
Table 3. Condensed Fukui functions e1r and e2r and local softness
(s1r and s2r) values at the donor nitrogen atom of amines calculated at
the B3LYP/6–31111G**//B3LYP/6–311G* level
1
was dried under vacuum and the IR and H NMR spectra were
Amine
eþx
sþx
eꢀx
sꢀx
obtained. Similar experiments were also carried out at ꢀ158C or at
room temperature (,258C) followed by refluxing in methylene
chloride (boiling point 408C) for 1 h for all the amines.
The reaction mixtures of the secondary amines and maleic
anhydride in acetonitrile on prolonged refluxing followed by
column chromatography and recrystallization from methanol
afforded the corresponding maleimic acid derivatives (16) in a
pure state.
1a (Z ¼ 0.123, s ¼ 4.063)
1b (Z ¼ 0.148, s ¼ 3.372)
1c (Z ¼ 0.143, s ¼ 3.495)
1d (Z ¼ 0.141, s ¼ 3.556)
1e (Z ¼ 0.145, s ¼ 3.454)
ꢀ0.365
ꢀ1.483
ꢀ1.511
ꢀ1.148
ꢀ0.647
ꢀ0.874
ꢀ0.041
ꢀ0.167
1.511
ꢀ0.448
ꢀ0.332
ꢀ0.182
ꢀ0.253
0.448
ꢀ0.247
ꢀ0.286
ꢀ0.302
ꢀ0.854
ꢀ1.017
ꢀ1.043
Compound 15a (in mixture with 16a): IR: umax (KBr, cmꢀ1
)
3408 (O-H s), 1575 (C=O s), 1193 (C-O s); 1H NMR (300 MHz,
H
H
3
2
1
CDCl3, TMS, d ppm, J Hz): d 8.43 (bs, OH), d 6.13 (d, JHH
H
11.7, 1H, C(2)H), 6.08 (d, 3JHH 11.7, 1H, C(3)H), 5.30 (s, 3H,
N-CH3), 2.41 (t, 3JHH 4.8, 4H, C(2’)H2), 2.27 (t, 3JHH 4.8, 4H,
C(1’)H2).
C
O
H
3
Acrolein
η = 0.19
s = 2.65
Compound 16a: Yield: 92 %; mp 168–1708C; IR: umax (KBr,
cmꢀ1) 3450 (O-H s), 1611 (C=O s), 1100 (C-O s); H NMR
1
(400 MHz, [D4]methanol, TMS, d ppm, J Hz): d 6.34 (d, 3JHH
11.2, 1H, C(2)H), 6.07 (d, 3JHH 11.2, 1H, C(3)H), 4.90 (s, OH),
3.31(t, 3JHH 3.2, 4H, C(1’)H2), 3.30 (t, 3JHH 3.2, 4H, C(2’)H2),
2.74 (s, 3H, N-CH3); 13C NMR (75.48 MHz, [D4]methanol, d
ppm): 171.30 (C(1)=O), 170.11 (C(4)=O), 132.19 (C2), 130.97
(C3), 44.24 (C20), 42.92 (C10), 39.17 (CH3); HRMS: m/z 198.21;
[M]þ requires 198.22 .
ϩ
ϩ
Ϫ
Ϫ
fx
sx
fx
sx
C1 Ϫ2.250
0.662 Ϫ0.097 Ϫ0.257
0.161 Ϫ0.003 Ϫ0.008
C2
0.061
C3 Ϫ0.215 Ϫ0.569 Ϫ0.029 Ϫ0.077
Compound 15b (in mixture with 16b): IR: umax (KBr, cmꢀ1
)
Fig. 2. Condensed Fukui functions at different carbon atoms of the
3416 (O-H s), 1555 (C=O s), 1216 (C-O s); 1H NMR (300 MHz,
acrolein molecule.
CDCl3, TMS, d ppm, J Hz): d 8.19 (bs, OH), 6.19 (d, 3JHH 11.9,
3
3
1H, C(2)H), 6.04 (d, JHH 11.9, 1H, C(3)H), 3.26 (t, JHH 4.8,
4H, C(1’)H2), 2.69 (t, 3JHH 4.8, 4H, C(2’)H2).
resultingcarbonyl addition productsisomerize to the N-substituted
maleimic acid derivatives, which are stabilised due to amidic
delocalization of the nitrogen lone pair. Thus, in contrast to the
acyclic a,b-unsaturated carbonyl compound, no addition occurs
across the C=C functionality of maleic anhydride.
Compound 16b: Yield: 78 %; mp 162–1648C; IR: umax (KBr,
1
cmꢀ1) 3400 (O-H s), 1585 (C=O s), 1163 (C-O s); H NMR
3
(400 MHz, [D4]methanol, TMS, d ppm, J Hz): d 7.34 (d, JHH
15.4, 1H, C(2)H), 6.74 (d, 3JHH 15.4, 1H, C(3)H), 4.95 (s, OH),
3.70 (t, 3JHH 6.4, 4H, C(1’)H2), 3.55 (t, 3JHH 6.4, 4H, C(2’)H2);

1252
M. Kour, R. Gupta and R. K. Bansal
(a)
(b)
H9
H8
C3
C4
C2
C5
O6
O7
O1
Fig. 3. (a) LUMO and (b) electrostatic potential map of the maleic anhydride molecule.
(a)
(b)
H10
II1
H14
H12
C13
C4
H3
N5
H11
H2
H15
C17
N18
H19
H8
H7
II16
Fig. 4. (a) HOMO and (b) electrostatic map of 1-methylpiperazine.
13C NMR (75.48 MHz, [D4]methanol, d ppm): 167.73 (C(1)=O),
164.03 (C(4)=O), 134.94 (C2), 131.56 (C3), 26.22 (C10), 24.45
(C20); HRMS: m/z 170.18; [MþH]þ requires 170.18.
3.36 (q, 3JHH 6.7, 1H, CHDHECH3), 2.96 (q, 3JHH 7.2, 2H, CH2),
1.28 (t, 3JHH 7.2, 3H, CH3), 1.16 (t, 3JHH 7.2, 3H, CH3).
Compound 15c (in mixture with 16c): IR: umax (KBr, cmꢀ1
)
Computational Methods
3412 (O-H s), 1576 (C=O s), 1113 (C-O s); 1H NMR (300 MHz,
All calculations were carried out at the DFT level using the
B3LYP hybrid functional.[46,47] All geometries were optimized
in the gas phase at the B3LYP/6–31þG(d) level of the theory,
using the Gaussian 03 suite of programs.[48] Frequency calcu-
lations were performed at the same level to determine zero-point
correction energies and to characterise the minima by the
presence of no imaginary frequencies. The natural bond orbital
(NBO)[49] analysis was employed for determining MPA.
CDCl3, TMS, d ppm, J Hz): d 8.58 (bs, OH), 6.23 (d, 3JHH 11.9,
3
1H, C(2)H), 6.14 (d, JHH 11.9, 1H, C(3)H), 3.87 (t, 3JHH 4.8,
4H, C(1’)H2), 3.13 (t, 3JHH 4.8, 4H, C(2’)H2).
Compound 16c (contains traces of 15c): Yield: 82 %; mp
134–1368C; IR: umax (KBr, cmꢀ1) 3480 (O-H s), 1609 (C=O s),
1105 (C-O s); 1H NMR (400 MHz, [D4]methanol, TMS, d ppm,
J Hz): d 7.34 (d, 3JHH 15.2, 1H, C(2)H), 6.67 (d, 3JHH 15.2, 1H, C
(3)H), 4.89 (s, OH), 3.82 (t, 3JHH 4.8, 4H, C(1’)H2), 3.69 (t, 3JHH
4.8, 4H, C(2’)H2); HRMS: m/z 186.18; [MþH]þ requires
186.18.
Conflicts of Interest
Compound 15d116d: IR: umax (KBr, cmꢀ1) 3430 (O-H s),
The authors declare no conflicts of interest.
1586 (C=O s), 1181 (C-O s); 1H NMR (300 MHz, CDCl3, TMS,
3
d ppm, J Hz): d 9.3 (bs, OH), 6.21 (d, JHH 12.0, 1H, C(2)H),
6.08 (d, 3JHH 12.0, 1H, C(3)H), 3.43 (t, 3JHH 6.9, 2H, C(50)H2),
3.36 (t, 3JHH 6.9, 1H, C(1’)H), 2.96 (q, 3JHH 7.2, 1H, C(2’)H),
Supplementary Material
IR and 1H NMR spectra of the products; Cartesian coordinates
of the geometries optimized (Table S1) and energies of all the
species in the gas phase at the B3LYP/6–311þþG* level and
zero-point correction at the B3LYP/6–31þG* level (Table S2);
total energies, ionization potential, electron affinity, hardness
and softness of 1a–e (Table S3); Mulliken atomic charges and
Fukui functions (Tables S4–S11); and FMOs and electrostatic
3
1.25 (m, 2H, C(30)H2), (C(4’)H2 merged), 1.14 (d, JHH 7.2,
3H, CH3).
Compound 15e116e: IR: umax (KBr, cmꢀ1) 3429 (O-H s),
1580 (C=O s), 1194 (C-O s); 1H NMR (300 MHz, CDCl3, TMS,
d ppm, J Hz): d 8.9 (bs, OH), 6.23 (d, 3JHH 12.0, 1H, C(2)H), 6.09
3
3
(d, JHH 12.0, 1H, C(3)H), 3.43 (q, JHH 7.1,1H, CHDHECH3),

Reaction of Secondary Amines with Maleic Anhydride
1253
potential maps of maleic anhydride and amines are available on
the Journal’s website.
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Acknowledgements
We are grateful to the authorities of the IIS University, Jaipur, India, for
providing the necessary facilities. We acknowledge gratefully the help of Mr
Priyadarshi Pathodiya, Therachem, Jaipur, India, in performing the NMR
spectroscopy studies.
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