Synthesis, structural and conformational study of some amides derived from N-methylpiperazine

Article abstract of DOI:10.1016/j.molstruc.2005.10.025

Some amides (1-6) derived from N-methylpiperazine were synthesized and studied by IR, ¹H and ¹³C NMR spectroscopy. In CDCl₃ solution, at room temperature, a fast interconversion of the piperazine ring with the N-CH₃

Full text of DOI:10.1016/j.molstruc.2005.10.025

Journal of Molecular Structure 787 (2006) 8–13
www.elsevier.com/locate/molstruc
Synthesis, structural and conformational study of some amides
derived from N-methylpiperazine
a
a
b
I. Iriepa a, , A.I. Madrid , E. Galvez , J. Bellanato
*
´
a
´
´
´
Departamento de Quımica Organica, Universidad de Alcala, Madrid, Spain
b Instituto de Estructura de la Materia, C.S.I.C., Madrid, Spain
Received 15 July 2005; received in revised form 18 October 2005; accepted 26 October 2005
Available online 19 December 2005
Abstract
Some amides (1–6) derived from N-methylpiperazine were synthesized and studied by IR, 1H and 13C NMR spectroscopy. In CDCl3 solution, at
room temperature, a fast interconversion of the piperazine ring with the N–CH3 group in equatorial position can be proposed. a,b-unsaturated
compounds 4 and 5 adopt in liquid state and in solution (CCl4, CCl2aCCl2, CDCl3) both s-cis and s-trans conformations.
q 2005 Elsevier B.V. All rights reserved.
Keywords: N-methylpiperazine; Amides; Infrared spectroscopy; NMR spectroscopy; Conformational analysis
1. Introduction
2. Experimental
The synthesis of amides derived from piperazine is a subject
of interest as several derivatives of this heterocyclic unit have
been found to possess important applications in biology [1–3].
As continuation of our studies on the synthesis, spectral
properties [4–7] and CoMFA (Comparative Molecular Field
Analysis) [8] of heterocyclic compounds with potential
therapeutic activity, we report in this paper the synthesis and
the structural study using IR and NMR spectroscopies of a
series of amides derived from N-methylpiperazine (Scheme 1).
The unambiguous assignment of all proton and carbon
resonances was achieved through the application of one
dimensional selective NOE (Nuclear Overhauser Effects),
two dimensional NMR techniques-homonuclear NOESY and
NMR spectra were recorded in CDCl3 on a Varian UNITY-
1
5OOFT spectrometer (499.843 MHz for H and 125 MHz for
13C). The standard vendor supplied gHSQC pulse sequences
were used. The double resonance experiments involved the use
of conventional irradiation, and were performed on a Varian
Mercury spectrometer (299.949 MHz).
The IR spectra of compounds 1–6 were recorded on a
Perkin–Elmer FTIR 1725X spectrophotometer, assisted by a
computer, between KBr windows in the 4000–400 cmK1
region and in CDCl3 solution (w0.15 M) in the 4000–
900 cmK1 region using 0.2 mm NaCl cells. Spectra of
compounds 4 and 5 were also registered in CCl4 and
CCl2aCCl2 solution at various concentrations. The reported
heteronuclear H–13C gHSQC (gradient Heteronuclear Single
wavenumbers are estimated to be accurate to within G3 cmK1
.
1
Quantum Correlations) correlated spectroscopy—and DR
(double resonance) experiments. The existence of s-cis and s-
trans conformations of a,b,-unsaturated compounds (4, 5) has
been determined with the aid of NOE in NMR and solvent
effects on the IR carbonyl band.
2.1. Synthesis
The synthesis of compounds 1–6 is summarized in
Scheme 1.
A solution of 1-methylpiperazine (10 mmol) in dry
tetrahydrofurane (10 mL) was added to a stirred mixture of
the corresponding acyl chloride (10 mmol) and triethylamine
in tetrahydrofurane (10 mL) at 0 8C. The reaction mixture was
allowed to warm to room temperature with continued stirring
for 2–5 h. Filtration and removal of solvent under reduced
*
Corresponding author. Tel.: C34 91 8854651; fax: C34 91 8854686.
E-mail address: isabel.iriepa@uah.es (I. Iriepa).
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.10.025

I. Iriepa et al. / Journal of Molecular Structure 787 (2006) 8–13
9
R
1
N
5
NH
RCOCl
NEt3
6
O
N
N
4
3
2
1´
CH3
CH
CH3
CH3
CH2
2´
3´
6´
5´
HC
C
CH2-CH3
C
CH3
1
R =
CH3
CH3
4
4´
2
3
5
6
Scheme 1. Synthesis of amides 1–6.
pressure afforded a yellow oil that was purified by treatment
with diethyl ether.
compound 4 is similar to those of compounds 1 ,2, 3, 5 and 6
except for the multiplets at 3.50–3.75 ppm and 3.31–3.52 ppm
where overlapping resonances, centered at 3.52 ppm, were
observed.
3. Results and discussion
3.1. NMR spectra
The singlet at 2.17–2.27 ppm has been assigned to the
N–CH3 protons in all compounds.
For the assignment of the signals corresponding to the C2,
C6, C3 and C5 protons, NOE and DR experiments for
compound 3 have been performed.
3.1.1. Spectral analysis and assignment
1
The H NMR spectra of compounds 1, 2, 3, 5 and 6 show
Saturation of the proton of the isopropyl group showed NOE
enhancements in the two signals, which appear at low field (3.41
and 3.51 ppm) (Fig. 1). Taking into account the gHSQC data
(Fig. 2), these signals correspond to protons of two different
carbons (C6 and C2 protons). Taking also into account the
anisotropic and the steric effects exerted by the amide group, the
signal at lower field (3.51 ppm) has been assigned to H2ax(H2eq)
and the signal at higher field (3.41 ppm) to H6ax(H6eq).
The multiplets centered at 2.30 and 2.34 ppm are assigned to
the C3 and C5 protons. Double resonance experiments have
been used to clarify the assignments of the signals correspond-
ing to these protons. By irradiation of the H2ax(H2eq) signal
(3.51 ppm), the multiplet at 2.30 simplifies to a singlet and,
great similarity being slightly different the spectrum of
compound 4.
The assignment of proton and carbon resonances for
compounds 1–6 was made on the basis of DR, NOE, NOESY
and gHSQC experiments. The values of the 1H NMR chemical
shifts were deduced by analysis of the respective spin systems.
These values with the signal assignments are listed in Table 1.
The 13C data are tabulated in Table 2.
1
In the H NMR spectra of compounds 1, 2, 3, 5 and 6 the
signals corresponding to the piperazine moiety appear as a
singlet at 2.17–2.27 ppm, two partially overlapped multiplets at
2.21–2.32 ppm and 2.24–2.42 ppm and two multiplets at 3.50–
3.75 ppm and 3.31–3.52 ppm. The 1H NMR spectrum of
Table 1
1H NMR chemical shifts (d, ppm) and multiplicities for compounds 1–6, in CDCl3
d (ppm)a
1
2
3
4
5
6
s-cis
s-trans
s-cis
s-trans
b
b
b
b
b
H2ax(H2eq) (m)
H6ax(H6eq) (m)
H3ax(H3eq) (m)
H5ax(H5eq) (m)
N–CH3 (s)
3.50
3.52
3.51
3.52
3.57
3.41
2.26
2.30
2.20
–
3.62
3.32
2.26
2.30
2.19
–
3.75
3.31
3.38
3.41
3.52
3.39
2.21
2.30
2.30
2.32
2.30
2.24
2.30
2.34
2.32
2.42
2.17
2.20
2.18
2.25
2.27
COCH3
1.94 (s)
–
–
–
–
–
–
–
–
CH2CH3
–
–
–
–
–
–
–
–
–
2.20 (m)
–
–
–
–
–
CH2CH3
1.02 (t)
–
–
–
–
–
CH(CH3)2
–
–
–
–
–
–
–
2.66 (m)
–
–
–
–
CH(CH3)2
0.99 (d)
–
b
–
–
–
–
CH3–CaCH2
CH3–CaCH2
CHaC(CH3)2
CHaC(CH3)2
Ph
–
–
–
–
–
1.88 (s)
5.12 (s), 4.96 (s)c
–
–
–
b
–
–
–
–
–
–
–
–
–
1.78 (d), 1.73 (d)d 2.07 (d), 1.80 (d)d
–
5.67 (s)
–
6.13 (s)
–
–
7.35 (m)
a
Abbreviations: d, doublet; m, multiplet; t, triplet; s, singlet.
Not determined due to the low resolution of the signals.
H in cis disposition with respect to the CH3 group.
CH3 in cis disposition with respect to the vinyl proton.
b
c
d

10
I. Iriepa et al. / Journal of Molecular Structure 787 (2006) 8–13
Table 2
13C NMR chemical shifts (d, ppm) for compounds 1–6, in CDCl3
1
2
3
4
5
6
s-cis
s-trans
s-cis
s-trans
C5
56.21
54.40
45.26
40.89
46.52
54.71
54.33
44.81
40.99
45.60
55.09
54.54
45.01
41.26
45.77
53.34a
53.95b
53.80b
45.75
40.18
44.88
169.83
–
54.99
55.15
55.07
55.07
47.25
41.69
45.69
C3
53.67a
54.60
54.46
C6
45.00
41.19
40.93
C2
42.06
25.76
27.68
N–CH3
44.78
45.85
46.18
CO
168.63
172.78
174.87
169.00
166.95
167.57
170.16
COCH3
CH2CH3
CH2CH3
CH(CH3)2
CH(CH3)2
CH3–CaCH2
CH3–CaCH2
CH3–CaCH2
CHaC(CH3)2
CHaC(CH3)2
CHaC(CH3)2
C10
29.89
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
26.25
–
–
–
–
–
–
9.35
–
–
–
–
–
–
–
29.79
–
–
–
–
–
–
19.28
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
17.11
19.47
–
–
–
–
104.17
114.12
–
–
–
–
133.84
139.54
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
19.99
23.34, 21.35
–
–
118.89
123.43
–
–
145.13
145.72
–
–
–
–
–
–
–
–
–
–
135.66
128.32
126.89
129.53
C20(60)
C30(50)
C40
–
–
–
–
a,b
These values may be interchanged.
therefore, this signal can be assigned to H3ax(H3eq). More-
over, saturation of the signal corresponding to H6ax(H6eq)
(3.41 ppm) simplifies the signal at 2.34 ppm; therefore, this
signal must correspond to H5ax(H5eq). It can be noted that the
spectrum of compound 3 shows only a signal for H2ax and
H2eq, H6ax and H6eq, H3ax and H3eq and H5ax and H5eq as
can be deduced by gHSQC data, what has also been observed
for compounds 1, 2, 4–6. This fact suggests a conformational
dynamics of the piperazine ring, which is fast enough on the
NMR time-scale to give one average signal. To assess this
b. A restricted rotation around the N–CO bond is deduced.
c. The a,b-unsaturated amides 4 and 5 exist in two nearly
planar s-cis and s-trans conformations.
These conclusions are supported by the following exper-
imental data:
–The N–CH3 1H chemical shifts of compounds 1–6 of 2.17–
2.27 ppm have the same values as those found in equatorial N–
CH3 substituted piperazines [9] and related compounds
[10–12]. Moreover, selective NOESY as well as selective
irradiation of the N–CH3 group for compound 4 show
exclusively correlations with H3 and H5 but not with H2 and
H6. In the case of an axially standing methyl group, NOEs
between the protons of the methyl group and H2ax, H6ax
should occur.
1
suggestion H NMR at K50 8C for compound 4 has been
performed, no significative changes having been observed.
1
Bearing in mind the similarity of the H NMR spectra for
the amide 3 and the other amides (1, 2, 4–6), the complete and
unambiguous assignment of the individual protons for the
piperazine system of amides 1–6 has been made (Table 1).
For the assignment of 13C NMR chemical shifts (Table 2),
substituent and electronic effects were taken into consideration.
Once the resonances of the respective protons were established,
the analysis of the gHSQC spectrum of 3 allowed the
interpretation of the chemical shifts values of the different
carbons of compounds 1–6.
–The N–CH3 13C chemical shifts of compounds 1–6 of
44.78–46.52 ppm are in agreement with previously reported
values in related compounds with an equatorial disposition of
this group [10–12].
As said before, the presence of one signal for the axial and
equatorial protons of the piperazine ring suggests a
3.1.2. Conformational study
CH3
H3C
We used 1H and 13C NMR techniques along with one
dimensional selective NOE, NOESY and variable temperature
experiments, to analyse the conformations of compounds 1–6
and the following general features were deduced:
H
1
N
5
H
6
H3C
H
O
3
N
2
4
H
a. In CDCl3 solution, at room temperature, a fast interconver-
sion of the piperazine ring with an equatorial position of
the N–CH3 group can be proposed.
H
Fig. 1. NOE enhancements in compound 3.

I. Iriepa et al. / Journal of Molecular Structure 787 (2006) 8–13
11
Fig. 2. gHSQC spectrum of compound 3.
Fig. 3. 1H NMR spectrum of compound 5.

12
I. Iriepa et al. / Journal of Molecular Structure 787 (2006) 8–13
conformational dynamics for the piperazine ring [9]. Tem-
perature dependent experiments for compound 4 support this
hypothesis. When the temperature was lowered at K50 8C, the
resolution of the signals in the H NMR spectrum does not
increase, suggesting a fast exchange regime between
conformations.
H
H
H3C
H
H
CH3
H
H
1
H
N
H
H
H
N
H3C
H3C
O
O
H
H
N
N
H
H
H
H
–The non-equivalence of the C2 and C6 protons and also of
the C2 and C6 accounts for a restricted rotation around the N–
CO amide bond.
s-trans
s-cis
Fig. 5. s-cis and s-trans conformations of compound 4.
–The a,b,-unsaturated amides 4 and 5 can adopt in solution
1
two nearly planar s-cis and s-trans conformations. The H
In the case of the a-CH3 substituted amide 4, the presence of
the s-cis and s-trans conformations (Fig. 5) cannot be deduced
from the 1H NMR spectrum due to the broadening of the
signals. However, the 13C NMR data in CDCl3 solution for this
compound show the existence of both conformations being the
s-trans (the most sterically favoured) the preferred confor-
mation (s-cis/s-transZ10:90).
NMR spectrum of 5 in CDCl3 at room temperature contains
two sets of signals (Fig. 3); consequently, these duplicity can
be attributed to the presence of the two conformations differing
in their arrangement around the CaC bonds.
The signals corresponding to the s-cis and s-trans confor-
mations have been assigned by NOE experiments (Table 1). We
may expect an observable NOE for the vinyl proton in the amide
5 with the s-cis conformation but not with the s-trans (Fig. 4).
Experimentally, the signal at 5.67 ppm (vinyl proton) shows
NOE with the signals at 3.57, 3.41 and 1.73 ppm, and therefore
these signals correspond to the s-cis conformation. The signal at
3.57 ppm has been assigned to H2ax and H2eq, the signal at
3.41 ppm to H6ax and H6eq, and finally, the signal at 1.73 ppm
to the CH3 group, in a cis disposition with respect to the vinyl
proton. The signal at 1.78 ppm must correspond to the CH3
group, in a trans disposition.
3.2. IR spectra
According to the literature [13] the carbonyl stretching
frequencies of the N,N-dialkylsubstituted amides are a little
lower than those of the monosubstituted amides. IR and NMR
studies on the conformation of a,b-unsaturated N,N-dimethyl
amides have shown the existence of nearly planar s-cis and s-
trans conformations [14]. The s-cis conjugated compounds
have normally markedly higher frequencies than the s-trans.
The tertiary amides 1–6 are characterized by the presence of
a very strong band in the 1623–1644 cmK1 region in the
‘liquid’ state and at 1614–1635 cmK1 in CDCl3 solution,
assigned to the carbonyl group (nCaO). The low frequencies
of the CO bands indicate a strong amide bond, so a restricted
rotation of the OaC–R residue can be assumed. These results
are in agreement with the NMR conclusions.
The signal at 6.13 ppm only shows NOE with the signal at
1.80 ppm; therefore these signals correspond, respectively, to
the vinyl proton and the CH3 group in a relative cis position, of
the s-trans conformation. The signal at 2.07 ppm is assigned to
the CH3 group in a trans disposition with respect to the vinyl
proton.
The signals at 2.26 and 2.30 ppm corresponding to
H3ax(H3eq) and H5ax(H5eq), respectively, for both s-cis and
s-trans conformations, appear partially overlapped.
The amides 1–3 with an alkyl group show the nCaO band at
1635–1644 cmK1 in liquid state and at 1625–1635 cmK1 in
CDCl3 solution. As expected, compound 6 absorbs at lower
frequency (1632 cmK1 in liquid state, and 1622 cmK1 in
CDCl3) than 1–3 as a result of conjugation of the carbonyl
group with the aromatic nucleus. Moreover, in this case the
characteristic aromatic bands of a monosubstituted aromatic
ring are present in the spectrum (i.e. 3000–3100; 1470–
1605 cmK1, etc.).
In our working conditions and taking into account the
relative proportions of the 1H NMR signals for both s-cis and s-
trans conformations, we can deduce that both conformers are
present in the amounts of 61% (s-cis) and 39% (s-trans).
The 13C NMR spectrum of compound 5 also shows two sets
of signals (Table 2). These results are in agreement with the
existence of both s-cis and s-trans conformers.
As it could be anticipated, in the case of the a,b,-unsaturated
compounds 4, 5 the carbonyl frequency varies with the
conformation (nearly planar s-cis or s-trans). The infrared
spectra of compound 4 show a strong band at 1623 cmK1 in the
liquid state and at 1617 cmK1 in CDCl3 solution, which is
assigned to the carbonyl band of the nearly planar s-trans form.
In both cases, a weaker band (shoulder) at higher frequency
(about 1645 cmK1) is attributed to the s-cis conformation. The
relative intensity of this band increases in carbon tetrachloride
solution (1649 cmK1) and even more in tetrachloroethylene
solution (1653 cmK1). Consequently, the relative intensity of
the s-trans band decreases. Moreover, the frequency of this
band (1617 cmK1 in CDCl3) is shifted to 1628 (CCl4) or
CH3
H3C
CH3
CH3
H
H
H
H
H
H
H
N
H
N
H3C
O
O
H3C
H
H
N
N
H
H
H
H
s-trans
s-cis
Fig. 4. s-cis and s-trans conformations of compound 5. NOE effects for the
vinyl proton in the s-cis conformation.

I. Iriepa et al. / Journal of Molecular Structure 787 (2006) 8–13
13
1630 cmK1 (CCl2aCCl2), respectively, what can also be
attributed to a solvent effect.
Acknowledgements
A.I. Madrid thanks the University of Alcala for a research
´
fellowship. J. Bellanato thanks Spanish Direccion General de
These results suggest the existence of equilibrium between
the s-cis and the s-trans conformers, the proportion of the latter
increasing in the liquid and in CDCl3 solution.
´
´
Investigacion (MEC), Project FIS2004-00108, for partial
financial support.
The n(CaC) bands could not be detected in the infrared
spectra, probably due to overlapping by the strong n(CaO)
bands.
Finally, a weak band at 3062–3066 cmK1 is assigned to the
CH2a group (antisymmetric stretch).
The infrared spectrum of compound 5 shows a strong band
at 1626 cmK1 in the liquid state which is shifted to 1615 cmK1
in CDCl3 solution, and as in compound 4 is assigned to a
twisted s-trans conformation. A shoulder at higher frequencies
(about 1665 cmK1) is attributed to the presence of a s-cis form.
Contrary to results in 4, the spectra in this region do not change
much in CCl4 or in CCl2aCCl2 solution except for the
increasing of the s-trans carbonyl frequencies (1634 or
1639 cmK1, respectively).
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been synthesized and their conformational preferences studied.
The 1H NMR spectra of the amides show only one signal for
axial and equatorial protons of the piperazine ring suggesting
an interconversion of this ring between conformations.
Besides, a preference of the N–CH3 group for an equatorial
position can be deduced.
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´ ´
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