Spectroscopic and theoretical studies of some 3-(4'-substituted phenylsulfanyl)-1-methyl-2-piperidones

Article abstract of DOI:10.3390/molecules18077492

The analysis of the IR carbonyl bands of some 3-(4'-substituted phenylsulfanyl)- 1-methyl-2-piperidones 1-6 bearing substituents: NO₂ (compound 1), Br (compound 2), Cl (compound 3), H (compound 4) Me (compound 5) and OMe (compound 6) supported by B3LYP/6-31+G(d,p) and PCM calculations along with NBO analysis (for compound 4) and X-ray diffraction (for 2) indicated the existence of two stable conformations, i.e., axial (ax) and equatorial (eq), the former corresponding to the most stable and the least polar one in the gas phase calculations. The sum of the energy contributions of the orbital interactions (NBO analysis) and the electrostatic interactions correlate well with the populations and the νCO frequencies of the ax and eq conformers found in the gas phase. Unusually, in solution of the non-polar solvents n-C₆H₁₄ and CCl₄, the more intense higher IR carbonyl frequency can be ascribed to the ax conformer, while the less intense lower IR doublet component to the eq one. The same νCO frequency trend also holds in polar solvents, that is νCO _(eq) < νCO _(ax). However, a reversal of the ax/eq intensity ratio occurs going from non-polar to polar solvents, with the ax conformer component that progressively decreases with respect to the eq one in CHCl₃ and CH₂Cl₂, and is no longer detectable in the most polar solvent CH₃CN. The PCM method applied to compound 4 supports these findings. In fact, it predicts the progressive increase of the eq/ax population ratio as the relative permittivity of the solvent increases. Moreover, it indicates that the computed νCO frequencies of the ax and eq conformers do not change in the non-polar solvents n-C₆H₁₄ and CCl ₄, while the νCO frequencies of the eq conformer become progressively lower than that of the ax one going from CHCl₃ to CH₂Cl₂ and to CH₃CN, in agreement with the experimental IR values. The analysis of the geometries of the ax and eq conformers shows that the carbonyl oxygen atom of the eq conformer is free for solvation, while the O_[CO]·H_[o-Ph] hydrogen bond that takes place in the ax conformer partially hinders the approach of the solvent molecules to the carbonyl oxygen atom. Therefore, the larger solvation that occurs in the carbonyl oxygen atom of the eq conformer is responsible for the observed and calculated decrease of the corresponding frequency. The X-ray single crystal analysis of 2 indicates that this compound adopts the most polar eq geometry in the solid. In fact, in order to obtain the largest energy gain, the molecules are arranged in the crystal in a helical fashion due to dipole moment coupling along with C-H·O and C-H·π_Ph hydrogen bonds.

Full text of DOI:10.3390/molecules18077492

Molecules 2013, 18, 7492-7509; doi:10.3390/molecules18077492
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Spectroscopic and Theoretical Studies of Some
3-(4′-Substituted phenylsulfanyl)-1-methyl-2-piperidones
Paulo R. Olivato 1,*, Jean M. M. Santos 1, Bruna Contieri 1, Carlos R. Cerqueira Jr. 1,
Daniel N. S. Rodrigues 1, Elisângela Vinhato 2, Julio Zukerman-Schpector 3 and Maurizio Dal Colle 4
1
Conformational Analysis and Electronic Interactions Laboratory, Institute of Chemistry,
University of São Paulo, USP, CP 26077, 05513-970 São Paulo, SP, Brazil;
E-Mails: jean.miguel10@gmail.com (J.M.M.S.); brunacontieri@hotmail.com (B.C.);
carloscerq@gmail.com (C.R.C.); dannopper@gmail.com (D.N.S.R.)
2
Institute for Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo,
UNIFESP, Diadema 09972-270, SP, Brazil; E-Mail: vinhato@iq.usp.br
3
Chemistry Department, Federal University of São Carlos, CP 676, 13565-905, São Carlos, SP, Brazil;
E-Mail: julio@ufscar.br
4
Department of Chemistry, University of Ferrara, Ferrara 44100, Italy; E-Mail: mau@unife.it
* Author to whom correspondence should be addressed; E-Mail: prolivat@iq.usp.br;
Tel.: +55-11-3091-2167; Fax: +55-11-3815-5579.
Received: 31 May 2013; in revised form: 20 June 2013 / Accepted: 21 June 2013 /
Published: 27 June 2013
Abstract: The analysis of the IR carbonyl bands of some 3-(4′-substituted phenylsulfanyl)-
1-methyl-2-piperidones 1–6 bearing substituents: NO2 (compound 1), Br (compound 2), Cl
(compound 3), H (compound 4) Me (compound 5) and OMe (compound 6) supported by
B3LYP/6-31+G(d,p) and PCM calculations along with NBO analysis (for compound 4)
and X-ray diffraction (for 2) indicated the existence of two stable conformations, i.e., axial
(ax) and equatorial (eq), the former corresponding to the most stable and the least polar
one in the gas phase calculations. The sum of the energy contributions of the orbital
interactions (NBO analysis) and the electrostatic interactions correlate well with the
populations and the νCO frequencies of the ax and eq conformers found in the gas phase.
Unusually, in solution of the non-polar solvents n-C6H14 and CCl4, the more intense higher
IR carbonyl frequency can be ascribed to the ax conformer, while the less intense lower IR
doublet component to the eq one. The same νCO frequency trend also holds in polar
solvents, that is νCO (eq) < νCO (ax). However, a reversal of the ax/eq intensity ratio occurs
going from non-polar to polar solvents, with the ax conformer component that

Molecules 2013, 18
progressively decreases with respect to the eq one in CHCl3 and CH2Cl2, and is no longer
7493
detectable in the most polar solvent CH3CN. The PCM method applied to compound 4
supports these findings. In fact, it predicts the progressive increase of the eq/ax population
ratio as the relative permittivity of the solvent increases. Moreover, it indicates that the
computed νCO frequencies of the ax and eq conformers do not change in the non–polar
solvents n-C6H14 and CCl4, while the νCO frequencies of the eq conformer become
progressively lower than that of the ax one going from CHCl3 to CH2Cl2 and to CH3CN, in
agreement with the experimental IR values. The analysis of the geometries of the ax and eq
conformers shows that the carbonyl oxygen atom of the eq conformer is free for solvation,
…
while the O[CO] H[o-Ph] hydrogen bond that takes place in the ax conformer partially hinders the
approach of the solvent molecules to the carbonyl oxygen atom. Therefore, the larger solvation
that occurs in the carbonyl oxygen atom of the eq conformer is responsible for the observed
and calculated decrease of the corresponding frequency. The X-ray single crystal analysis of 2
indicates that this compound adopts the most polar eq geometry in the solid. In fact, in order to
obtain the largest energy gain, the molecules are arranged in the crystal in a helical fashion due
to dipole moment coupling along with C-H…O and C-H…πPh hydrogen bonds.
Keywords: conformational analysis; infrared spectroscopy; theoretical calculations;
3-(4′-substituted phenylsulfanyl)-1-methyl-2-piperidones; X-ray crystal structure
1. Introduction
The analysis of the infrared (νCO) band and theoretical B3LYP/6-311++G(d,p) calculations of some
N,N-diethyl-2-[(4′-substituted) phenylsulfanyl acetamides Et2NC(O)CH2SC6H4-Y (Y=OMe, Me, H,
Cl, Br, NO2) [1] indicated the existence of two pairs (anti and syn) of cis (c) and gauche (g)
conformers in the gas phase, with the gauche conformers being significantly more stable (ca. 90%)
than the cis ones. The anti-geometry is more stable than the syn one for each pair of cis and gauche
conformers. The summing up of the σC-S→π*C=O, πC=O→σ*C-S, π*C=O→σ*C-S (NBO) orbital
interactions is the main factor that stabilises the gauche conformers to a larger extent than the cis ones
for which these interactions are absent. The similarity of the carbonyl frequencies in the gas phase for
the anti and syn pairs of the cis and gauche conformers originates a carbonyl doublet in solution for
which the less intense, higher frequency component is ascribed to the pair of the cis conformers and
the lower frequency component corresponds to the more stable pair of the gauche conformers.
In solution of the non-polar solvents (n-C6H14 and CCl4), the least polar gauche conformers (ca. 85%)
are predominant with respect to the most polar cis ones. In the polar solvent, CHCl3, a decrease of the
gauche/cis population ratio is observed, i.e., 60% / 40%, and in the highly polar solvent, CH3CN, the
most polar cis conformer is the only one present. This trend was supported by the PCM solvation
model performed by the B3LYP/6-311++G(d,p) method.
Theoretical and spectroscopic (IR, NMR and microwave) studies [2–5] of 2-piperidones showed
that the piperidone ring lies in a half-chair or slightly twisted half-chair conformation. X-ray single
crystal structure determination of the 3-chloro-2-piperidone [6] has shown that the piperidone ring is in

Molecules 2013, 18
7494
a slightly twisted half-chair conformation with the 3-substituent assuming the quasi-equatorial
[Cl-C-C=O (dihedral angle) = −30°] geometry. Moreover, our theoretical and X-ray single crystal
studies of some 3-(4′-substituted phenylsulfonyl)-1-methyl-2-piperidones [7,8] have shown that, in
these compounds, the 2-piperidone ring assumes a slightly distorted half-chair conformation. In the gas
phase the 3-substituent adopts the quasi-equatorial, sin-clinal and quasi-axial geometries with respect
to S-C-C=O dihedral angles of ca. 31°, 46° and 71°, respectively, while in the solid state the preferred
geometry is quasi-axial with respect to the S-C-C=O dihedral angle of ca. 72°.
Aiming to throw more light on the nature of the orbital and electrostatic interactions that influence
the stability of the cis-gauche conformers of 2-(4′-substituted)-phenylsulfanylamides [1], this paper
reports the IR study of some six-member ring lactams, i.e., 3-(4′-substituted phenylsulfanyl)-1-methyl-
2-piperidones bearing in the 4′ position the substituents, i.e., Y = NO2 (compound 1), Br (compound 2), Cl
(compound 3), H (compound 4) Me (compound 5) and OMe (compound 6) (Scheme 1) along with
density functional theory (DFT), polarizable continuum model (PCM) and natural bond orbital (NBO)
calculations for 4 taken as the representative compound for the whole series, along with the X-ray
diffraction analysis of 2. These compounds were chosen taking into account some conformational
rigidity of the piperidone ring, which allows the 3-substituent to assume almost exclusively the
quasi-equatorial and axial conformations.
Scheme 1. Atom labeling of 3-(4′-substituted phenylsulfanyl)-1-methyl-2-piperidones and
definition of relevant torsion angles.
α = O(1)-C(2)-C(3)-S(4)
β = C(2)-C(3)-S(4)-C(20)
γ = C(3)-S(4)-C(20)-C(25)
δ = O(1)-C(2)-N(6)-C(10)
θ = O(1)-C(2)-N(6)-C(7)
θ’ = O(1)-C(2)-C(3)-C(9)
ω = C(2)-N(6)-C(7)-C(8)
ω’ = C(2)-C(3)-C(9)-C(8)

Molecules 2013, 18
7495
2. Results and Discussion
Table 1 displays the stretching frequencies and the absorbance percentage of the analytically
resolved carbonyl band components for compounds 1–6 in solvents of increasing relative permittivity [9],
i.e., n-C6H14 (ε = 1.9), CCl4 (ε = 2.2), CHCl3 (ε = 4.8), CH2Cl2 (ε = 9.1) and CH3CN (ε = 38). A
doublet is shown in n-hexane for derivatives 2–6 and in CCl4 (fundamental and first overtone regions)
for derivatives 1–6, with the higher frequency component being the more intense, i.e., ca. 80% and
ca. 58%, respectively. However, as the relative permittivity increases, a reversal of the carbonyl
doublet intensity is observed, with the lower frequency component progressively increasing up to ca.
70% in CHCl3, ca. 88% in CH2Cl2 and emerges as a singlet in the highest relative permittivity solvent,
CH3CN. The solvent effect on the carbonyl band components for 4, chosen as a prototype for the series
1–6 is illustrated in Figure 1.
Figure 1. IR spectra of 3-(phenylsulfanyl)-1-methyl-2-piperidone (4) showing the analytically
resolved carbonyl stretching band in: n-hexane (a), carbon tetrachloride [fundamental (b) and
first overtone (c)], chloroform (d) dichloromethane (e) and acetonitrile (f).
0.7
0.6
0.5
0.4
0.3
0.2
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
(a)
(b)
0.1
0
1710 1700 1690 1680 1670 1660 1650 1640 1630 1620
1720
1700
1680
1660
1640
1620
1600
0.06
(c)
0.05
1.2
(d)
1.0
0.04
0.03
0.02
0.01
0
0.8
0.6
0.4
0.2
0
3350 3340 3330 3320 3310 3300 3290 3280 3270 3260 3250 3240
1670 1660 1650 1640 1630 1620 1610 1600
1690
1680
Wavenumber (cm-1)
Wavenumber (cm-1)

Molecules 2013, 18
7496
Figure 1. Cont.
0.9
0.8
(f)
(e)
0.8
0.7
0.6
0.5
0.4
0.7
0.6
0.5
0.4
0.3
0.2
0.3
0.2
0.1
0
0.1
0
1690 1680 1670 1660 1650 1640 1630 1620 1610 1600
1690 1680 1670 1660 1650 1640 1630 1620 1610 1600
Wavenumber (cm-1)
Wavenumber (cm-1)
The unusual observed solvent effect (Table 1) might not be a clear evidence of the existence of
conformational isomerism. However, the occurrence of two carbonyl band components in the first overtone
region for 1–6 in carbon tetrachloride, with comparable intensity ratios and at frequencies twice that of the
fundamental minus ca. 15 cm−1 (that is two times the mechanical anharmonicity [10]), is indicative of the
occurrence of two stable conformations for all compounds in this solvent, ruling out the existence of any
vibrational effect in the fundamental transition of the νCO mode [11,12]. Therefore, the IR data strongly
suggest the occurrence of two conformers for compounds 1–6 in all solvents, with the exception of
CH3CN, for which only one conformer is present.
Table 1. Frequencies (ν, cm−1) and intensities of the carbonyl stretching bands in the IR
spectra of 3-(4′-substituted-phenyl)sulfanyl-1-methyl-2-piperidones 1–6.
Compound
Y
n-C6H14
Pa
CCl4
CHCl3 CH2Cl2 CH3CN
ν
c
ν
Pa νb
P
ν
P
ν
P
ν
P
1
2
3
4
5
6
NO2
-
- 1660 61 3300 60 1648 43 1656 9
-
-
-
- 1652 39 3289 40 1637 57 1641 91 1645 100
Br 1668 84 1658 68 3299 63 1645 33 1652 12
1656 16 1650 32 3291 37 1635 67 1641 88 1644 100
Cl 1668 79 1660 45 3306 49 1647 30 1656 13
1656 21 1652 55 3292 51 1635 70 1641 87 1644 100
1669 83 1659 62 3300 59 1647 32 1656 9
1654 17 1651 38 3290 41 1635 68 1641 91 1644 100
Me 1668 72 1657 57 3300 57 1645 16 1652 12
1659 28 1651 43 3286 43 1634 84 1640 88 1643 100
OMe 1668 78 1660 44 3301 41 1647 25 1652 15
1657 22 1651 56 3288 59 1635 75 1639 85 1643 100
-
-
-
-
H
-
-
-
-
-
-
a
b
Relative intensity of each component of the carbonyl doublet, expressed as a percentage of absorbance; First
overtone; c Compound slightly soluble in this solvent.
Aiming to estimate the geometry of the minimum energy conformations in the gas phase, B3LYP/
6-31+G(d,p) calculations were performed for compound 4, taken as representative of the whole series 1–6.
Moreover, in order to estimate the solvent effect on the minimum energy conformations of 4, the PCM
method was applied to fully optimise the referred conformations in the n-C7H16, CCl4, CHCl3, CH2Cl2 and

Molecules 2013, 18
7497
CH3CN solvents, and to compute the corresponding vibrational frequencies. The relevant data obtained for
4 are presented in Table 2.
Theoretical calculations in the gas phase show the existence of two stable conformations for
compound 4. Due to the significant contribution of the [-O‒C=N+] resonance structure for the
hybrid [13,14], the [C(O)NC(10)C(7)] carboxamide moiety (Scheme 1) is almost planar (δ and θ
dihedral angles are ca. 3° and ca. 170°, respectively). This induces the piperidone ring to adopt a
slightly distorted half-chair geometry, with the ω and ω′ dihedral angles being ca. 27° and ca. 51°,
respectively (Table 2 and Figure 2) and the 3-phenylsulfanyl substituent assuming the almost axial
(ax) and equatorial (eq) geometries with respect to the carbonyl group, at α angles of ca. 83° and
ca. 29°, respectively. Moreover, as shown by the θ, θ′, ω and ω′ dihedral angles for the equatorial
conformer (Table 2), in the gas phase of 4 and in the solid state of 2, the substituents at the 4′ position
have no influence on the geometry of the lactam moiety.
Table 2. Relative energies (E, kJ mol−1), dipole moments (μ, D), carbonyl frequencies
(ν, cm−1), and selected torsion angles (deg) calculated for the minimum energy conformations
of 3-phenylthio-1-methyl-2-piperidone 4 in gas phase and in solvents with the PCM
method at the B3LYP/6-31+G(d,p) level, and the X-ray geometric data of 2.
Torsion angles/º d
Conf. a E b P c
μ
νCO
α
β
γ
δ
θ
θ’
ω
ω'
gas
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
eq
-
0
96.8 3.62 1713.4 82.0
8.45 3.2 5.39 1720.1 30.4
84.4 4.08 1696.7 82.0
4.20 15.6 6.21 1699.0 31.6
80.0 4.16 1694.2 81.9
−101.3
−176.5
−101.9
−177.4
−102.1
−176.2
−102.4
−178.1
−104.3
−178.4
−105.6
−178.4
48.2
73.2
48.4
72.9
49.1
73.3
47.7
72.1
48.5
71.4
48.9
70.7
2.13
167.9
−170.8
168.2
−172.2
168.1
−171.7
168.3
−174.9
169.3
−174.3
169.8
−173.2
−154.3
157.1
23.6
−50.8
50.8
−3.90
2.06
−23.7
23.3
C7H16
CCl4
0
−154.5
158.2
−50.7
50.3
−3.74
2.06
−22.8
23.4
0
−154.5
157.7
−50.7
50.6
3.43 20.0 6.37 1694.3 31.1
0.17 48.3 4.61 1676.8 81.9
−3.75
2.11
−23.1
23.2
CHCl3
CH2Cl2
CH3CN
X-ray e
−154.5
159.9
−50.7
49.7
0
51.7 7.20 1673.0 33.4
2.01 30.8 4.89 1668.9 80.6
69.2 7.62 1663.8 32.7
3.93 16.9 5.18 1659.5 80.0
−3.28
2.57
−20.6
23.1
−155.7
159.1
−50.1
50.9
0
−3.20
2.60
−20.8
22.6
−156.2
158.5
−49.8
50.2
0
-
83.1 8.10 1652.3 32.1
−3.11
−21.7
-
-
-
31.0 (3) −176.2 (2) −155.5(2) −4.1 (4) −177.6(3) 157.2(3) −14.3(4) 53.1 (3)
a Conformer designations ax and eq refers to the axial and equatorial conformers, respectively; b Relative energy; c Molar
fraction in percentage; d See Scheme 1; e Refers to compound 2.
The ax conformer is the most stable (ca. 97%) and the least polar (ca. 3.6 D) and the eq conformer
is the least stable (ca. 3%) and the most polar (ca. 5.4 D). Moreover, in the gas phase of 4, the carbonyl
frequencies for the ax and eq conformers are ca. 1713 cm−1 and ca. 1720 cm−1, respectively. As
expected, this trend is in agreement with the computations of the N,N-diethyl-2-[(4′-substituted)
phenylsulfanyl acetamides [1] for which, in the gas phase, the less polar gauche conformers are the
most stable (lower carbonyl frequency) than the more polar cis conformers (higher carbonyl
frequency) (see above). However, the theoretical (gas phase) carbonyl frequencies and the relative
population values for the axial and equatorial conformers for 4 (Table 2) do not match with the IR
frequencies and the relative intensities of each carbonyl component in solution (Table 1). Unusually, it

Molecules 2013, 18
7498
seems reasonable to assign the more intense (ca. 80%) higher carbonyl frequency component in
solution of non-polar solvent (n-C6H14) to the ax conformer and the less intense lower carbonyl
frequency component to the eq one.
Table 2 shows that the torsional angles α-ω’ for the ax and eq conformers for 4 remain almost the
same going from the gas phase to solvents of increasing relative permittivity, i.e., from n-C7H16 to
CH3CN. Furthermore, in this direction, there is a progressive decrease of the calculated ax/eq
conformer population ratio, i.e., 97%/3% (gas), 84%/16% (n-C7H16), 80%/20% (CCl4), 48%/52%
(CHCl3), 31%/69% (CH2Cl2) and 17%/83% (CH3CN) followed by a simultaneous decrease of carbonyl
frequency shifts (Δν = νeq – νax) between the eq and ax conformer frequencies that is: ca. 7 cm−1 (gas),
ca. 2 cm−1 (n-C7H16), ca. 0 cm−1 (CCl4), ca. −4 cm−1 (CHCl3), ca. −5 cm−1 (CH2Cl2) and ca. −7 cm−1
(CH3CN). These trends cannot be justified on the grounds of the dipole moment (μ) analysis as the
dipole moment for the ax and eq conformers increases almost to the same extent going from gas to
acetonitrile solution, i.e., ca. 2.7 D.
A close match was not found between the computed ax/eq population ratios (PCM) and the
experimental IR ones. However, the progressive decrease of the prevalence of the population of the ax
conformer over the eq one going from n-C7H16 to CCl4, along with the progressive increase of the
prevalence of the population of the eq conformer over the ax one going from CHCl3 to CH2Cl2 and to
CH3CN, seems to be in line with the experimental IR trend of the ax/eq population ratio. The fact that
the calculated (PCM) carbonyl frequencies for the ax and eq conformers becomes practically
coincident in the non-polar solvents n-C7H16 and CCl4, and that the νCO frequency of the eq conformer
becomes progressively smaller than the νCO frequency of the ax conformer going from CHCl3 to CH2Cl2
and to CH3CN, gives support to the experimental (IR) ax-eq carbonyl frequencies assignments (see above).
It should be pointed out that MP2/6-31+G(d,p) calculations for 4 [15] have shown that the
population ratio for the ax/eq conformers (ca. 78%/22%) as well as the torsional angles α-ω’ values for
both conformers, are close to those obtained at the B3LYP/6-31+G(d,p) level (Table 2). The computed
MP2 carbonyl frequencies indicate that the ax and eq conformers have almost the same carbonyl
frequency of ca. 1716 cm−1. Moreover the single-point PCM calculations at the MP2 level [16] for the
ax and eq conformers of 4 have shown that the solvent effect on the ax/eq population ratio is quite
similar to that obtained with the B3LYP method.
Table 3 presents the ChELPG atomic charges [17] for selected atoms computed at the B3LYP/6-
31+G(d,p) level for compound 4, while Table 4 displays the interatomic distances between some selected
atoms and the difference between these contacts and the sum of the van der Waals (ΣvdW) radii.
Table 3. ChElPG charge (e) at selected atoms obtained at the B3LYP/6-31+G(d,p) level
for 3-phenylsulfanyl-1-methyl-piperidone 4.
Conf. O(1)
C(2)
S(4)
N(6) H(26) H(30) H(5) H(11) H(16) H(17)
ax
eq
−0.557 0.525 −0.321 −0.187 0.131 0.102 0.048 0.088 0.028 0.065
−0.537 0.605 −0.320 −0.311 0.103 0.061 0.027 0.058 0.030 0.045

Molecules 2013, 18
7499
Table 4. Selected interatomic distances (Å) for the ax and eq conformers of
3-phenylsulfanyl-1-methyl-2-piperidone 4 at the B3LYP/6-31+G(d,p) level.
Conf. a O[1]...S[4] b
O[1]...H[11] d
2.28
O[1]...H[26] d
2.35
O[1]...H[5] d
Δl c
Δl
Δl
Δl
ax
eq
3.37
2.89
+0.05
−0.44
−0.37
2.52
2.83
−0.20
2.27
4.75
−0.43
−0.45
+2.03
+0.11
a Conformer designation; b Sum of the van der Waals radii = 3.32 Å; c Difference between non bonded atoms
distance and the sum of their van der Waals radii; d Sum of the van der Waals radii = 2.72 Å.
Due to the decrease of the α dihedral angle going from the ax (ca. 80°) to the eq (ca. 31°)
conformer there is in the eq conformer a short contact between the negatively charged
O[1] (≅ −0.55e)…S[4] (≅ −0.32e) atoms whose interatomic distance is significantly shorter than the
sum of the van der Waals radii (ΣvdW) (Δl ≅ −0.43Å) while for the ax conformer the same contact is
close to the ΣvdW radii (Δl ≅ +0.05Å). The referred shorter O…S contact of the eq conformer should
be responsible for the stronger Repulsive Field Effect [11,18] between the Cδ+=Oδ- and Cδ+─Sδ−
dipoles in the eq conformer, being responsible for both the destabilisation of this conformer relative to
the ax one and for the higher carbonyl frequency observed in the gas phase of the eq conformer with
respect to that of the ax one whose carbonyl frequency shift (νeq – νax) is ca. +7 cm−1 (Table 2).
As expected from the geometry of the carboxamide moiety of the 1-methyl-2-piperidones, there is a
short contact between the oppositely charged O[1] (≅ −0.55e)…H[11] (≅ 0.09e) atoms whose
interatomic distance is significantly shorter than the ΣvdW radii (Δl ≅ −0.44Å; C-H…O angle ca. 103°)
for both ax and eq conformers (Figure 2). The O[1] (≅ −0.55e) and H[5] (≅ 0.05e) contact is shorter
than ΣvdW radii by (Δl ≅ −0.20Å; C-H…O angle ca. 84°) for the ax conformer only. Moreover, as a
consequence of the smaller γ dihedral angle in the ax conformer (ca. 48°) as compared with that of the
eq one (ca. 73°) for 4 (Table 2) the positively charged o-phenylsulfanyl hydrogen atom H[26]
(≅ 0.13e) gets closer to the negatively charged carbonyl oxygen atom O[1] (≅ −0.55e) Therefore, the
interatomic distance becomes shorter than the ΣvdW radii by (Δl ≅ −0.37 Å; C-H…O angle ca. 148°)
for the ax conformer and larger than the ΣvdW radii (Δl ≅ +2.0 Å) for the eq one.
Figure 2. Axial (ax) (a) and equatorial (eq) (b) conformers for 4 obtained at the B3LYP/
6-31+G(d,p) level.
From these Hδ+…Oδ- contacts analysis it may be concluded that the O[1]…H[11] short contact
stabilises electrostatically both the eq and ax conformers to the same extent. However, the O[1]…H[5]
contact and mainly the O[1]...H[26] one stabilise electrostatically the ax conformer only.

Molecules 2013, 18
7500
In order to rationalise the orbital interactions that stabilise the ax and eq conformers, NBO
analysis [19] was performed and the results obtained for selected NBO energy interactions between
donor and acceptor orbitals [20] are reported in Table 5.
Table 5. Comparison of significant NBO energies (kcal mol−1) of the corresponding
interacting orbitals for the conformers ax and eq of 3-phenylsulfanyl-1-methyl-2-piperidone 4
at the B3LYP/6-31+G(d,p) level.
Orbitals
ax
eq
LPN6→π*C2=O1
LPO1→σ*C2-N6
LPO1→σ*C2-C3
LPO1→σ*C21-H26
LPO1→σ*C10-H11
LPO1→ σ*S4-C20
LPS4→ π*C2=O1
LPS4→ π *C20-C21
σC3-S4→π*C2=O1
σC3-S4→σ*C2-N6
πC2=O1→σ*C3-S4
π*C2=O1→σ*C3-S4
∑ Eb
65.3
25.4
18.9
3.0
50.6
25.5
20.3
-
1.2
0.9
-
2.7
0.7
3.4
0.6
0.8
106.7
1.0
a
-
2.0
8.3
4.2
-
1.7
5.5
135.3
a Interaction energy smaller than 0.5 kcal mol−1; b Summing up of the energies of the interacting orbitals.
The most important orbital interaction, the LPN6→π*C2=O1 corresponding to the [O=C–N ↔ −O–C=N+]
conjugation, has a value of ca. 65 kcal moL−1 for the ax conformer, significantly higher than that of ca.
51 kcal mol−1 for the eq one. The smaller orbital interaction value for the latter conformer is in
agreement with the smaller contribution of the [−O–C=N+] canonical form to the resonance hybrid due
to the strong Repulsive Field Effect between the Cδ+=Oδ- and Cδ+-Sδ− dipoles, as outlined above. On
the other hand, the very short Oδ−[1]…H δ+[13] contact with a suitable C─H…O angle of ca. 148° in the ax
conformer determines the LPO1→σ*C21-H26 orbital interaction (ca. 3 kcal mol−1) (hydrogen bond) in the ax
conformer. This interaction increases the weight of the polar [-O‒C=N+] canonical form for the resonance
hybrid and is partially responsible for the higher value of the LPN6→π*C2=O1 orbital interaction cited above.
In addition, the higher occupancy value [20] of the σ*C21-H26 orbital in the ax conformer (0.134 vs. 0.014)
gives further support for the occurrence of the significant LPO1→σ*C21-H26 hydrogen bond interaction.
In the carboxamide moiety, there are two additional higher energy interactions (through bond
coupling [21]), LPO1→σ*C2-N6 and LPO1→ σ*C2-C3, at mean values of ca.26 kcal mol−1 and
ca.20 kcal mol−1, respectively, for the eq and ax conformers.
The more favourable γ dihedral angle of the phenylsulfanyl group (ca. 48°) for the ax conformer
allows a reasonable 3pS-πPh* orbital overlap that contributes to a larger stabilisation of the ax
conformer with respect to the eq one [LPS4→π*C20-C21 orbital interaction of ca. 8.3 kcal mol−1 (ax) and
ca.2.7 kcal mol−1 (eq)].
The O[1]…H[11] short contacts are responsible for the weak LPO1→σ*C10-H11 orbital interactions of
ca. 1.1 kcal mol−1 that stabilise to the same extent both conformers.

Molecules 2013, 18
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It should be pointed out that the eq conformer is stabilised through two weak LPO1→σ*S4-C20 and
C3-S4→σ*C2-N6 orbital interactions whose delocalisation energy values are ca. 0.9 kcal mol−1 and
σ
3.4 kcal mol−1, respectively.
The suitable geometry of the ax conformer allows the occurrence of superjacent LPS4→ π*C2-O1
orbital interaction [22] whose value is 2.0 kcal mol−1, which is absent for the eq conformer. Moreover,
in the [O=C-C-S] moiety there are three π(π*)/σ(σ*) orbital interactions: πC2=O1→σ*C3S4
,
σ
C3-S4→π*C2=O1 and π*C2=O1→σ*C3-S4 whose energy values progressively decrease as the π/σ overlap
decreases, i.e., they present the maximum value for the ax conformer and the minimum one for the eq
one. In fact, the sum of the energies of these interactions displays the value ca.11.4 kcal mol−1 and
ca. 2.1 kcal mol−1 for the ax and eq conformers, respectively.
In conclusion, since the total sum of the delocalisation energies of the selected interactions has the
maximum value of ca. 135 kcal mol−1 for the ax conformer and significantly decreases to
ca. 107 kcal mol−1 for the eq one, the NBO analysis and the trend of the electrostatic interactions are in
agreement with the higher relative abundance of the ax (ca. 97%) conformer with respect to the eq
one, found in the gas phase, whose computed carbonyl frequencies are ca. 1713 cm−1 and
1720 cm−1, respectively.
However, there is no matching between the IR experimental and the theoretical gas phase data. As
pointed out above, since a reversal of the IR carbonyl frequencies has been observed experimentally in
solution, the higher frequency component has been ascribed to the ax conformer, while the lower
frequency component to the eq one. This behaviour may be rationalised as follows.
A close inspection of the ax (a) and eq (b) conformers in the gas phase (Figure 2 and Scheme 2)
shows that the eq conformer carbonyl oxygen atom is free for solvation, while the hydrogen bond that
takes place between the ortho-phenylsulfanyl hydrogen atom and the carbonyl oxygen atom lone pair
in the ax conformer partially prevents the solvent molecules' approach to the carbonyl oxygen atom.
Scheme 2. Differential solvent effect for 4 showing that the carbonyl oxygen atom in the
axial conformer (a) is partially hindered for the approach of the solvent molecules due to
[H(o-Ph)…O(CO)] hydrogen bond in comparison to the equatorial conformer (b) for which
the carbonyl oxygen atom is free for salvation.
H
δδ−
δδ−
δδ−
δδ+
δδ−
δδ+
H
H
δδ+
H
δδ+
δδ−
δδ−
H
δδ−
δδ−
(b)
δδ+
(a)
δδ+
δ−
δδ+
Oδ−
O
H
H
δδ+
N
Cδ+
Cδ+
N
H
Hδ+
H
H
H
H
H
S
H
H
H
H
H
H
S
H
H
H
H
H
H
H
H
H
ax
eq
H

Molecules 2013, 18
7502
Therefore, the larger solvation at the carbonyl oxygen atom in the more polar eq conformer
contributes to the decrease of the carbonyl bond order and, as a consequence, lowers its frequency to a
larger extent than that of the ax conformer.
X-ray single crystal analysis of 2 showed that in the solid state this compound assumes the
equatorial geometry with respect to the torsion angle α (Scheme 1) and the 2-piperidone ring, similar
to the gas phase of 4, displays a slightly distorted half-chair conformation (Table 2 and Figure 3).
Figure 3. The molecular structure of 2 showing atom labelling scheme and displacement
ellipsoids at the 50% probability level (arbitrary spheres for the H-atoms).
The absolute values of the relevant torsional angles (α-ω’) in the solid state of 2 (Table 2) are
similar to the corresponding torsional angles in the gas phase of the equatorial conformer of 4, except
for the absolute value of the γ angle of ca. 155° for 2, which differs from the γ angle of ca. 73° for 4.
The larger γ torsional angle for 2 allows the hydrogen bonding between the π phenyl orbital and the
methylene [H14] atom (Figure 4).
Figure 4. A view of the supramolecular array of 2 where the C-H…O and C-H….πPh
interactions are shown.

Molecules 2013, 18
7503
In fact, in order to obtain the largest energy gain from the crystal packing, the molecules of the
equatorial conformer of 2 are stabilised in the crystal through dipole moment coupling along with two
hydrogen bond interactions in a helical fashion, i.e., C-H…O (C3i-H5i…O1: C3i…O1 = 3.346(3),
H5i…O1 = 2.43 Å; C3i-H5i…O1 = 155°; symmetry operation i = 1/2 + x, 1/2-y, 1-z) and C-H…π (C7…Cgii =
3.618(4), H14…Cgii = 2.72 Å; C7-H14…Cgii = 155°; symmetry operation ii = x − 1/2, −1/2−y, 1 − z).
Additionally, similar to the gas phase of 4, in the crystal of 2 an intramolecular short contact
[C10-H11...O1: C...O = 2.676(4); H…O = 2.23 Å; C-H...O = 107°] was found.
3. Experimental
3.1. Materials
All solvents for IR measurements were spectrograde and used without further purification. The
3-[4′-substituted phenylsulfanyl)]-1-methyl-2-piperidones 1–3, 5 and 6 are new compounds.
Derivatives 2–6 were obtained from the reaction of 1-methyl-2-piperidone (a) with lithium
diisopropylamide (b), in tetrahydrofuran (THF), followed by the addition of the THF solution of
4-substituted diphenyl disulphide (c), in the presence of hexamethylphosphoramide (d), in the molar ratio
of 1(a):2(b):1(c):1(d) as described in the literature for 4 [23]. The appropriate diphenyl disulphide was
prepared by the reaction of 4-substituted-thiophenol with bromine in dichloromethane on hydrated
silica gel support [24]. The pure phenylsulfanyl piperidones 2–6 were obtained in 20–45% yield. The
4′-[nitrophenylsulfanyl]-1-methyl-2-piperidone 1 was obtained as follows: initially, the THF solution
of the lithium enolate of 1-methyl-2-piperidone obtained as described above [23] reacted with the
tosylate chloride [25] in a 1:1 ratio to obtain the 3-chloro-1-methyl-2-piperidone. This crude product
was allowed to react with an ethanolic solution of 4-nitrothiophenol in the presence of equimolar
proportion of potassium hydroxide. After usual workup and recrystallization from ethanol-water, the
pure compound 1 was obtained in 24% yield. Suitable crystals for X-ray analysis for 2 were obtained
1
13
by vapour diffusion from chloroform/n-hexane at 283K. The H- and C-NMR data for compounds
1–6 are collated in Table 6 and elemental analysis results are shown in Table 7.
3.2. IR Measurements
The IR spectra were obtained on a FTIR Michelson-Bomem-MB100 spectrophotometer, with 1.0 cm-1
resolution. The carbonyl region (1800–1600 cm−1) was recorded for n-hexane, carbon tetrachloride,
chloroform, dichloromethane and acetonitrile solutions, at a concentration of 2.0 × 10−2 mol dm−3,
using a 0.519 mm sodium chloride cell. The carbonyl first overtone region (3500–3100 cm−1) was
recorded for carbon tetrachloride and chloroform solutions (2.0 × 10−2 mol dm−3) using a 1.00 cm
quartz cell. The overlapped carbonyl bands (fundamental and first overtone) were deconvoluted by
means of the Grams/32 curve-fitting program, version 4.04 Level II [26]. The populations of the axial
and equatorial conformers were estimated from the maximum of each component of the resolved
carbonyl doublet expressed in percentage of absorbance, assuming equal molar absorptivity
coefficients for all the studied compounds 1–6, in each solvent.

Molecules 2013, 18
7504
Table 6. Physical, 1H- and 13C-NMR data for 3-[(4′-substituted-phenyl)sulfanyl]-1-methyl-
2-piperidones 1–6.
Compd.
1
Y
Mp (°C)
1H- and 13C-NMR a
NO2
77–78
1H-NMR: 8.14–8.12 (m, 2H), 7.64–7.63 (m, 2H), 4.06 (t, 1H, J = 5.5 Hz), 3.41–3.32
(m, 2H), 2.99 (s, 3H), 2.30–2.27 (m, 1H), 2.09–2.03 (m, 2H), 1.92–1.88 (m, 1H).
13C-NMR: 167.83, 146.07, 145.77, 128.67, 123.86, 49.82, 46.90, 35.36, 28.68, 20.76.
1H-NMR: 7.44–7.40 (m, 4H), 3.82 (t, 1H, J = 5.7Hz), 3.33–3.26 (m. 2H), 2.96 (s, 3H),
2.11–2.04 (m, 2H), 1.99–1.94 (m, 1H), 1.82–1.77 (m, 1H).
2
3
4
5
6
Br
Cl
64–64
13C-NMR: 168.36, 134.27, 134.07, 132.19, 121.82, 50.06, 49.02, 35.47, 28.83, 20.59.
1H-NMR: 7.53–7.51 (m, 2H), 7.30–7.29 (m, 2H), 3.84 (t, 1H, J = 5.7Hz), 3.36–3.28
(m, 2H), 2.99 (s, 3H), 2.17–2.08 (m, 2H), 2.02–1.96 (m, 1H), 1.83–1.80 (m, 1H)
13C-NMR: 168.19, 133.77, 133.64, 133.33, 129.06, 49.86, 48.96, 35.27, 28.62, 20.38.
1H-NMR: 7.56–7.54 (m, 2H), 7.32–7.28 (m, 2H), 7.26–7.24 (m, 1H), 3.88 (t, 1H, J = 5.0 Hz),
3.30–3.24 (m, 2H), 2.97 (s, 3H), 2.12–2.07 (m, 2H), 1.98–1.94 (m, 1H), 1.77–1.74 (m, 1H).
13C-NMR: 168.47, 134.96, 132.61, 129.12, 127.61, 50.08, 49.03, 35.44, 28.75, 20.46.
1H-NMR: 7.47–7.46 (m, 2H), 7.15–7.13 (m, 2H), 3.83 (t, 1H, J = 5,5Hz), 3.34–3.25 (m, 2H),
2.98 (s, 3H), 2.35 (s, 3H), 2.13–2.05 (m, 2H), 1.96-1.92 (m, 1H), 1.80–1.75 (m, 1H)
13C-NMR: 168.37, 137.77, 133.25, 130.79, 129.71, 49.89, 49.21, 35.23, 28.35, 21.12, 20.12.
1H-NMR: δ (ppm): 7.51–7.49 (m, 2H), 6.85–6.83 (m, 2H), 3.79 (s, 3H), 3,71 (t, 1H,
J = 6,0Hz), 3.25–3,23 (m, 2H), 2.94 (s, 3H), 2.10–2,01 (m, 2H), 1.94–1,89 (m, 1H),
1.75–1,71 (m, 1H).
b
H
38–39
CH3
OCH3
44–45
b
13C-NMR: 168.36, 159.85, 135.93, 124.61, 114.50, 55.31, 49.89, 49.80, 35.20, 28.28, 20.12
a 1H- and 13C- chemical shifts in ppm relative to TMS and coupling constants in Hz at 500 MHz. in CDCl3;
b liquid at room temperature; c From [4]: b.p 130–133° / 0.05 Torr.
Table 7. Elemental analysis data for 3-[(4′-substituted-phenyl)sulfanyl]-1-methyl-2-
piperidones 1–6.
Compd
Y
NO2
Br
Molecular
formula
Analysis (%)
H
54.12 5.30 10.52
C
N
1
2
3
4
5
6
C12H14N2O3S
Calc.
Found 54.34 5.23 10.46
C12H14BrNOS
C12H14ClNOS
C12H15NOS
C13H17NOS
C13H17NO2S
Calc.
Found 47.91 4.77
Calc. 56.35 5.52
Found 56.26 5.22
Calc. 65.12 6.83
Found 65.12 6.56
Calc. 66.34 7.28
Found 66.23 7.20
Calc. 62.12 6.82
Found 62.13 6.81
48.01 4.70
4.67
4.79
5.48
5.27
6.33
6.46
5.95
6.01
5.57
5.55
Cl
H
CH3
OCH3
3.3. X-ray Measurements
Crystal data for C12H14BrNOS (2): M = 300.21, T = 290(2) K, orthorhombic, P212121, a = 7.3328(5),
b = 7.7903(6), c = 21.502(2)Å, V = 1228.30(17) Å3, Z = 4, Dx = 1.623 g cm−3, F(000) = 608,
λ (Mo Kα) = 0.71073, μ = 3.495 mm−1, R = 0.0275.

Molecules 2013, 18
7505
3.3.1. Data Collection and Processing
Data were collected on a Bruker APEX-II CCD diffractometer using Mo Kα radiation so that
max = 25.4°, no. of unique data = 2229, no. of parameters = 146, R (1964 data with I ≥ 2σ(I)) = 0.0275, wR
θ
(all data) = 0.0663. The structure was solved by direct methods [27] and refined with anisotropic
displacement parameters for non- hydrogen atoms. The H atoms were geometrically placed
(C—H = 0.93–0.98 Å) and refined as riding with Uiso(H) = 1.2–1.5Ueq(C). The weighting scheme
2
2
used was w = 1/[σ2(Fo ) + 0.0193P2 + 0.000P] where P = (Fo + 2Fc2)/3) with SHELXL-97 [28] on F2.
The programs WinGX [29], ORTEP3 for Windows [30], PLATON [31], MarvinSketch 5.1.10 [32]
and DIAMOND [33] were used for geometric calculations and to prepare crystallographic material for
publication and depositing. Crystallographic data for the structural analysis have been deposited with
the Cambridge Crystallographic Data Centre as CCDC 934425. Copies of this information may be
obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: 44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
3.4. Theoretical Calculations
All calculations were carried out (at 298 K) using methods and basis sets implemented in the
GAUSSIAN package of programs (G03.E01) [34]. Full geometry optimisations (GJF files for the eq
and ax conformers of 4 are available in the Supplementary material as eq.gjf and ax.gjf) and analytical
vibrational frequency calculations were performed on all the orientations with respect to the carbonyl
group resultant from a systematic conformational search using the ab initio Hartree–Fock method with
the 3–21G basis set [35–39], allowing complete relaxation of all internal parameters. The obtained
conformations were refined using B3LYP and MP2 methods with the 6-31+G(d,p) basis set [35–39].
Frequency analyses were carried out to verify the nature of the minimum state of all the stationary
points obtained. To estimate the solvation effects on the relative stability of the most relevant
conformers, a full optimisation and frequency calculations were done starting from the gas-phase
optimised structures using the PCM model [40] at the B3LYP/6-31+G(d,p) level as implemented in the
GAUSSIAN 03. Additionally, the solvent effect was estimated by PCM single-point calculations
MP2/6-31+G(d,p) [41] using the corresponding gas-phase optimised structures. The NBO 3.1
program [19] was used as implemented in the GAUSSIAN 03 package, and the reported NBO
delocalisation energies (E2) are those given by second-order perturbation theory. The partial atomic
charges were calculated using a grid based method (ChElPG) [42].
4. Conclusions
The preferred conformations of some 3-(4′-substituted phenylsulfanyl)-1-methyl-2-piperidones 1–6
bearing as substituents NO2 (compound 1), Br (compound 2), Cl (compound 3), H (compound 4) Me
(compound 5) and OMe (compound 6) were determined by νCO IR analysis, B3LYP/6-31+G(d,p) and
PCM calculations along with NBO analysis (for 4) and X-ray diffraction (for 2). Theoretical data
indicated the existence of two stable conformations. The 2-piperidone ring of the title compounds
assumes a slightly distorted half-chair geometry, while the phenylsulfanyl substituent adopts the

Molecules 2013, 18
7506
almost axial (ax) and equatorial (eq) geometries with respect to the carbonyl group. The ax conformer
is the most stable (ca. 97%), the least polar, and exhibits a lower νCO frequency.
Unusually, the higher νCO frequency component can be ascribed to the ax conformer in solution of
non-polar (C6H14 and CCl4) and polar solvents (CHCl3 and CH2Cl2). As far as the relative abundance is
concerned, the ax conformer component progressively decreases with respect to the eq one as the
relative permittivity increases, and is no longer detectable in the most polar solvent CH3CN.
The PCM method was applied to derivative 4 to fully optimise the ax and eq conformations in all
solvents. The torsional angles α-ω’ of the ax and eq conformers remain practically the same going
from the gas phase to solvents of increasing relative permittivity.
The progressive decrease of the ax/eq population ratio as the solvent polarity increases is in line
with the experimental IR trend. Moreover, the computed PCM νCO frequencies of the two conformers
do not significantly differ in the non-polar solvents. In contrast, the νCO frequency of the eq conformer
becomes progressively smaller than that of the ax one as the solvent polarity increases. These results
further support the experimental IR frequency assignments. The lower νCO IR frequency of the eq
conformer in solution may be rationalised by the analysis of the computed geometries, which indicate
that in the eq conformer the carbonyl oxygen atom is free for solvation, while in the ax conformer the
…
presence of the [OCO Ho-Ph] hydrogen bond partially prevents the solvent molecules' approach to the
carbonyl oxygen atom. Thus, the larger solvation at the carbonyl oxygen atom of the most polar eq
conformer decreases the carbonyl bond order and consequently its frequency to a larger extent than in
the ax conformer.
The sum of the energy contributions of the orbital interactions (NBO analysis) and the electrostatic
interactions correlates well with the populations and the νCO frequencies of both conformers in the gas
phase. The smaller contribution of the LPN→π*CO orbital interaction for the eq conformer with respect
to the ax conformer is in line with the smaller contribution of the [−O‒C=N+] canonical form to the
resonance hybrid due to the strong Repulsive Field Effect between the Cδ+=Oδ− and Cδ+-Sδ− dipoles,
which destabilises the eq conformer and increases its νCO frequency relative to that of the ax conformer.
X-ray single crystal analysis of 2 indicates that this compound assumes, in the solid, the most polar
eq geometry with respect to the [O=C-C-SPh] moiety and that the 2-piperidone ring displays a slightly
distorted half-chair conformation. In order to obtain the largest energy gain from the crystal packing,
the molecules of the eq conformer of 2 are arranged in the solid through a helical fashion due to
hydrogen bond interactions, i.e., C(3)-H(5)…O(1) and C(7)-H(14)…π(Ph)
.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/7/7492/s1.
Acknowledgments
The Brazilian authors thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
for financial support of this research and for a fellowship to E.V., the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq) for scholarships to C.R.C.Jr., J.M.M.S., D.N.S.R.
and B.C. and fellowships to P.R.O and J.Z-S, and Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior CAPES (808/2009) to J.Z-S and for a scholarship to D.N.S.R.. The authors thank Prof.

Molecules 2013, 18
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R.H.A. Santos (IQSC-USP) for the X-ray data collection. The Italian author thanks MIUR (PRIN
2009) for financial support.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
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Sample Availability: Samples of the compounds 1–6 are available from the authors.
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