Synthesis, Molecular and Crystal Structure Analysis of 1-(4- Methylbenzenesulfonyl)indole-3-carbaldehyde and DFT Investigation of Its Rotational Conformers

Article abstract of DOI:10.3390/molecules19021990

Two independent molecules that differ in terms of rotation about the central S-N bond comprise the asymmetric unit of the title compound 1. The molecules have a V-shape with the dihedral angles between the fused ring system and benzene ring being 79.08(6)

Full text of DOI:10.3390/molecules19021990

Molecules 2014, 19, 1990-2003; doi:10.3390/molecules19021990
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis, Molecular and Crystal Structure Analysis of
-(4-Methylbenzenesulfonyl)indole-3-carbaldehyde and DFT
Investigation of Its Rotational Conformers
1
1
,
1
1
Julio Zukerman-Schpector *, Lucas Sousa Madureira , Glaudeston Dutra Wulf ,
2
2
3,4
3,
Hélio A. Stefani , Stanley N. S. Vasconcelos , Seik Weng Ng and Edward R. T. Tiekink *
1
Laboratório de Cristalografia, Estereodinâmica e Modelagem Molecular, Departamento de
Química, Universidade Federal de São Carlos, C.P.676, São Carlos, SP, 13565-905, Brazil;
E-Mails: lucassousamadureira@gmail.com (L.S.M.); glaudeston_@hotmail.com (G.D.W.)
2
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo,
0
5508-900, SP, Brazil; E-Mails: hstefani@usp.br (H.A.S.); stanleynsv@gmail.com (S.N.S.V.)
3
Department of Chemistry, The University of Malaya, Kuala Lumpur 50603, Malaysia;
E-Mail: mseikweng@um.edu.my
4
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 80203, Saudi Arabia
*
Authors to whom correspondence should be addressed; E-Mails: julio@power.ufscar.br (J.Z.-S.);
edward.tiekink@gmail.com (E.R.T.T.); Tel.: +60-3-7967-6775 (E.R.T.T.);
Fax: +60-3-7967-4193 (E.R.T.T.).
Received: 13 November 2013; in revised form: 25 January 2014 / Accepted: 28 January 2014 /
Published: 13 February 2014
Abstract: Two independent molecules that differ in terms of rotation about the central S-N
bond comprise the asymmetric unit of the title compound 1. The molecules have a
V-shape with the dihedral angles between the fused ring system and benzene ring being
79.08(6)° and 72.83(5)°, respectively. The packing is mostly driven by ··· interactions
occurring between the tolyl ring of one molecule and the C ring of the indole fused ring
6
system of the other. DFT and IRC calculations for these and related 1-(arylsulfonyl)indole
molecules showed that the rotational barrier about the S-N bond between conformers is
within the 2.5–5.5 kcal/mol range. Crystal data for C16
group Pna2 , a = 19.6152(4) Å, b = 11.2736(4) Å, c = 12.6334(3) Å, V = 2793.67(13) Å ,
Z = 8, Z' = 2, R = 0.034.
3
H13NO S (1): Mr = 299.33, space
3
1
Keywords: indole-3-carbaldehyde; conformational isomerism; DFT; IRC; crystal structure
analysis; X-ray diffraction

Molecules 2014, 19
. Introduction
Indoleamine 2,3-dioxygenase (IDO) is one of the three heme-containing dioxygenases [1]. This
1991
1
enzyme is involved in the kynurenine pathway which is the major pathway for the catabolism of the
essential amino acid tryptophan (Trp), being responsible for catalysing the rate-limiting step of the Trp
degradation to N-formylkynurenine [2]. Elevated Trp catabolism has been associated with
rheumathoid arthritis [3] and cancer [4]. It has been shown that after chemotherapy, inhibition of IDO
could delay the recurrence of tumour antigens tolerance [5], and also that its inhibition could be a new
route to improve immunity to leishmania-infected humans [6]. As part of our research aimed at the
synthesis of potential IDO inhibitors, using indole as a scaffold, 1-[(4-methylbenzene)sulfonyl]indole-
3
-carbaldehyde (1, Figure 1), was synthesized and its crystal structure determined.
Figure1. Chemical structures of (1) and (2).
In a previous contribution in this area [7], we reported the crystal structure of a closely related
compound, 3-ethenyl-1-[(4-methylbenzene)sulfonyl]indole (2), where an ethenyl moiety was in the
-postion rather than the carbaldehyde of compound 1 (Figure 1). It is noted that in both 1 and 2 there
3
are two independent molecules in the asymmetric unit, i.e., Z' = 2, and that in each case these are
conformers, each being related to each other via a rotation about the central S-N bond. As this situation
seemed unusual [8,9], a search of the Cambridge Structure Database (CSD) [10] was performed. For
all-organic molecules only, there were 148,842 hits for structures crystallising with Z' = 1 compared
with 20807 with Z' = 2, i.e., indicating examples of structures Z' = 2 are only 14% as likely to ocurr,
compared with structures with Z' = 1. With this background, a search was conducted for structures
related to 1, i.e., 1-(arylsulfonyl)indole derivatives, to ascertain how prevalent this phenomenon was
for this class of compound. The results of this survey are also presented herein. Finally, DFT
calculations on 1, 2 and related compounds were performed in order to understand the energetics of
these systems, in particular the nature of the rotational barrier around the S-N bond.
2
. Results and Discussion
There are two independent molecules in the asymmetric unit of 1 which are shown in Figure 2. The
dihedral angles between the fused ring system (r.m.s. deviations = 0.011 and 0.022 Å for the N1- and
N2-containing rings, respectively) and the benzene ring are close, i.e., 79.08(6)° and 72.83(5)°,
respectively. The values found in similar structures are 82.98(12)° and 84.46(13)° for the two
independent molecules of 3-ethenyl-1-(4-methylphenylsulfonyl)-1H-indole (2) [7]; 80.37(8)° for
(
2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)methanol [11], 77.41(5)° for ethyl 2-bromo-3-(1-phenyl-
sulfonyl-1H-indol-3-yl)acrylate [12] and 66.47(15)° for benzyl(3-bromo-1-(phenylsulfonyl)indol-2-
ylmethyl)(p-tolyl)amine [13]. In 1, each carbaldehyde moiety is almost co-planar with the ring to

Molecules 2014, 19
1992
which it is connected as seen in the values of the C8-C7-C9-O3 and C24-C23-C25-O6 torsion angles
of −175.4(2)° and −174.1(2)°, respectively. Further discussion on the relationship between the two
independent molecules in 1 is found below in the context of the DFT calculations performed on
these species.
Figure 2. Molecular structures for the two independent molecules of 1 showing the atom
numbering scheme.
The crystal structure features a range of intermolecular interactions as summarized in Table 1, with
the most significant of these being ··· interactions occurring between the tolyl ring of the
S1-containing molecule and the C ring of the indole fused ring system of the S2-containing molecule.
6
The two-molecule aggregates thus formed are connected into a supramolecular chain along the c-axis
via C-H···O interactions involving each of the sulfoxide-O atoms of the S2-containing molecule
whereby the O4 and O5 atoms accept H atoms bound to indole- and methyl- residues derived from the
S1- and S2-containing molecules, respectively. Links between these chains are of the type C-H··· and
6
involve a tolyl-H atom of the S1-containing molecule interacting with the C ring of the indole fused
ring system of the S2-containing molecule, resulting in the formation of supramolecular layers in the
bc-plane, as shown in Figure 3a. Links between layers are exclusively of the type C-H···O and involve
both aldehyde-O3 and O6 atoms as well as the sulfoxide-O2 atoms as acceptors, Figure 3b.
A search of the CSD [10,14] resulted in 34 related 1-(arylsulfonyl)indole structures of which five
have two independent molecules in the asymmetric unit, that is Z' = 2, a ratio consistent with the
general findings mentioned in the Introduction (see the Supplementary Material of this article for the
complete list of all 34 hits). Arguably, the most interesting of these structures are the (E)- and
(
Z)- conformers of ethyl 2-methyl-4-(1-((4-methylphenyl)sulfonyl)-1H-indol-3-yl)-4-(1-naphthyl)but-
-enoate [15] (Figure 4), where the (Z)- conformer crystallises with Z' = 1 (compound 3), while the (E)
2
conformer crystallises with Z' = 2 (compound 4). These molecules were also subjected to DFT
calculations along with 1 and 2, as described below.

Molecules 2014, 19
1993
Table 1. Geometric parameters describing intermolecular interactions (A–H···B; Å)
operating in the crystal structure of 1.
A
H
-
B
A‒H H···B
A···B
A‒H···B Symmetry Operation
Cg(C10–C15)
Cg(C17–C22)
-
-
3.5917(13) 1.41(11)
2 – x, 1 – y, ½ + z
x, y, – 1 + z
C3
C32
C31
C5
H3
O4
O5
0.95 2.56
0.98 2.55
0.95 2.99
0.95 2.58
0.95 2.40
0.95 2.60
0.95 2.33
3.370(3)
3.401(3)
3.901(2)
3.458(3)
3.129(3)
3.452(3)
3.175(3)
143
148
160
155
134
150
147
H32A
H31
H5
– x, 1 – y, – ½ + z
–x, 1 – y, ½ + z
Cg(C1–C6)
O2
½ – x, ½ + y, –½ + z
½ + x, ½ – y, z
C8
H8
O6
C25
C27
H25
H27
O3
–x, 1 – y, ½ + z
O3
½ – x, –½ + y, ½ + z
Figure 3. Views of the supramolecular association in the crystal structure of 1:
a) supramolecular layer in the bc-plane, and (b) in projection down the c-axis showing the
(
stacking of layers along the a-axis. The ···, C-H···O (within layers), C-H···O (between
layers), and C-H··· interactions (obscured in the (b) projection) are shown as purple,
brown, orange and blue dashed lines, respectively.
(a)
(b)
Figure 4. Chemical structures of ethyl 2-methyl-4-(1-((4-methylphenyl)sulfonyl)-1H-
indol-3-yl)-4-(1-naphthyl)but-2-enoate (3), the Z-conformer with Z' = 1, and 4, the
E-conformer with Z' = 2.
In all calculations the experimental structure, i.e., as determined by X-ray crystallography, was the
starting point for geometry optimisations. In cases where Z' = 2 and the independent molecules are

Molecules 2014, 19
1994
conformers, as is the cases of 1 and 4 [15], calculations, as well as the Intrinsic Reaction Coordinate
IRC) calculations, were performed for both molecules. For 2 [7], where the two independent
(
molecules were almost identical, the 180° related-conformer was generated. This was done so that
comparable IRC calculations for 2 could be performed as for 1 and 4. The two independent molecules
of 1 are conformers, being twisted about the S-N and S-C bonds (Figure 2). At this point it is important
1
to stress that the appearance of conformers is a solid-state effect. A variable temperature H-NMR
study was conducted (see Supplementary Material) down to −50 °C in deuterated chloroform solution
and no evidence was found for more than one conformation. As seen from the overlay diagram in
Figure 5, where the S1-containing molecule has been super-imposed upon the inverted form of the
S2-containing molecule using QMol [16], the molecular geometries closely resemble each other. The
major difference in the molecules is quantified in the C10-S1-N1-C8 and C26-S2-N2-C24 torsion
angles of 109.18(17)° and −116.34(18)°, respectively; a smaller difference in the O1-S1-C10-C11 and
O4-S2-C26-C27 torsion angles of −2.1(2)° and 6.1(2)°, respectively, is noted.
Figure 5. Superposition of the two independent molecules comprising the asymmetric
unit of 1 [16], drawn so that the SO groups are superimposed. The inverted form of the
2
S2-containing molecule (blue image) has been employed.
Geometry optimisation calculations conducted on the two independent molecules of each of 1 and 2
show that in each case both conformers optimise to the same energy-minimised molecule. This
observation is readily ascribed to the fact that in both cases the structures are stabilized by comparable
intramolecular C-H···O interactions as illustrated in Figures 6 and 7 and quantified in Table 2, where
the geometric parameters and NBO analyses of these interactions are listed.
Figure 6. Geometry optimised molecules for the (a) S1- and (b) S2-containing molecules
of 1. Details of the intramolecular C-H···O interactions are tabulated in Table 2.
(
a)
(b)

Molecules 2014, 19
1995
Figure 7. Geometry optimised molecules for the (a) S1- and (b) S1'-containing molecules
of (2). Details of the intramolecular C-H···O interactions are tabulated in Table 2.
(
a)
(b)
Table 2. Geometric parameters describing intramolecular interactions (A–H···B; Å, °) for (1) and (2).
−
1
A
H
B
A–H H···B A···B A‒H···B NBO energy/kcal·mol
1) S1-containing molecule
(
C2 H2 O1 1.10 2.35
C11 H11 O1 1.10 2.69
C8 H8 O2 1.09 2.71
C15 H15 O2 1.10 2.56
C5 H5 O3 1.10 2.65
3.05
3.08
3.05
3.00
3.25
120.2
99.7
−2.09
−0.29
−0.26
−0.60
−0.76
97.2
102.7
113.9
(
1) S2-containing molecule
C18 H18 O4 1.10 2.36
C27 H27 O4 1.10 2.70
C24 H24 O5 1.09 2.70
C31 H31 O5 1.10 2.56
C21 H21 O6 1.10 2.65
3.05
3.08
3.04
3.00
3.25
120.0
99.5
−2.01
−0.27
−0.27
−0.62
−0.74
97.4
102.8
113.9
(
2) S1-containing molecule
C9 H9 O2 1.10 2.32
C16 H16 O2 1.10 2.70
C8 H8 O1 1.09 2.71
C20 H20 O1 1.10 2.56
3.03
3.08
3.05
3.00
120.8
99.5
−2.32
−0.27
−0.25
−064
97.5
102.9
(
2) S1'-containing molecule
C9 H9 O1' 1.10 2.33
C20 H20 O1' 1.10 2.68
C8 H8 O2' 1.09 2.70
C16 H16 O2' 1.10 2.58
3.04
3.07
3.05
3.01
120.6
100.1
97.7
−2.22
−0.31
−0.28
−0.57
102.4
NBO data calculated using the Giambiagi-Mayer and Wiberg models show that the S-O bonds have
significant ionic character in both the energy minimised and in the transition state structures (Table 3),
+
−
indicating that S ‒O is the best Lewis structure description, rather than S=O. The consequence of this
is that each sulfoxide-O atom has three lone pairs. Moreover, the NBO results indicate that the strength
*
*
of the S-N bond is due to n
N N
→σ S-N and, and particularly, n →σ S-C hyperconjugative interactions
which do not persist in the transition state (Table 4). The S-N bond orders do not change

Molecules 2014, 19
1996
*
significantly upon rotation as the n →σ
interactions do not achieve significant -bond character
O
S-N
*
*
from the n
N
→σ S-C and n
N
→σ S-O conjugation (Tables 3 and 4), so that three-dimensional
hyperconjugation results.
a
Table 3. Bond orders calculated for the optimised and transition state structures 1 and 2 .
Giambiagi-Mayer bond orders
Bond
S-O
S-N
S-C
1–S1
1.778
0.666
0.744
1–S2
1.778
0.666
0.744
(1)TS1
1.771
0.651
0.742
(1)TS2
1.769
0.640
0.749
2–S1
1.776
0.677
0.742
2–S2
1.776
0.677
0.742
(2)TS1
1.770
0.661
0.741
(2)TS2
1.768
0.650
0.747
Wiberg bond index
Bond
S-O
S-N
S-C
1–S1
1–S2 (1)TS1
(1)TS2
1.482
0.560
0.701
2–S1
1.483
0.590
0.691
2–S2
1.483
0.590
0.691
(2)TS1
1.482
0.578
0.691
(2)TS2
1.484 1.484 1.484
0.580 0.580 0.568
1.481
0.569
0.698
0.694 0.694 0.693
a
Bond orders are only listed for O1, as those for O2 have identical values.
−1
Table 4. Stabilization energies (kcal·mol ) of hyperconjugative interactions in the
a,b
sulfonylgroup .
1
Interaction
1–S1
4.6
1–S2
4.7
(1)TS1
0.0
(1)TS2
0.0
*
N
n →σ
S-C
*
nN→σ
0.2
0.2
0.0
0.0
S-N
*
nN→σ
nN→σ
2.0
1.8
6.0
5.9
S-O1
*
1.6
1.7
6.5
6.4
S-O2
*
S-C
nO1 →σ
32.0
51.2
0.2
32.0
51.2
0.2
32.8
52.1
0.2
30.2
52.0
0.3
*
S-N
nO1 →σ
*
n →σ
O1
S-O1
S-O2
*
nO1 →σ
30.3
30.3
30.3
30.3
2
Interaction
2–S1
4.5
2-S2
4.5
(2)TS1
0.0
(2)TS2
0.0
*
N
n →σ
S-C
*
nN→σ
0.2
0.2
0.0
0.0
S-N
*
nN→σ
nN→σ
2.0
2.2
6.5
6.3
S-O1
*
2.0
1.8
6.5
6.0
S-O2
*
S-C
nO1 →σ
32.2
50.1
0.2
32.2
50.1
0.2
33.0
51.1
0.2
32.6
51.6
0.2
*
S-N
nO1 →σ
*
n →σ
O1
S-O1
S-O2
*
nO1 →σ
30.3
30.3
30.3
30.3
a
b
The oxygen lone pair interaction is the sum of interactions of the three lone pairs; The listed energy values
are those calculated for O1, as those for O2 have identical values.
Two transition states for 1 and 2 were found (TS1 and TS2, Figures 8 and 9), with C-N-S-C torsion
angles near 0° and 180° and energy barriers ca 2.5 and 5.5 kcal/mol, respectively (Table 5). The lone
pairs of TS1 have lower occupancies (Table 6) thus greater hyperconjugative effects than those of TS2

Molecules 2014, 19
1997
according to the NBO analysis (Table 4) and that higher delocalization explains why the TS1 has a
more stable structure.
Figure 8. IRC of the rotational barrier about the S-N bond in 1: (a) 1TS1 and (b) 1TS2. Insets
5
are the corresponding molecular structures Torsion angle (°) (Energy + 8.0 × 10 ) in kcal/mol.
(a)
(b)
Figure 9. IRC of the rotational barrier about the S-N bond in 2: (a) 2TS1 and (b) 2TS2.
Insets are the corresponding molecular structures.
(a)
(b)
According to Table 7, the nitrogen and oxygen lone pairs in the transition states have higher
repulsion than in the minimum energy structures. Therefore, the origin of the rotational barrier of these
*
sulfonamides lies in the strong hyperconjugative effects of n
N
→σ S-C in the S-N bond coupled with the
high repulsions between lone pairs in the transition state structures. This energy difference between the
transition states affords an effective Gibbs free energy of activation close to that of TS1, which ensures
that rotation occurs mainly via TS1. The relatively low rotational barrier indicates that there is a facile
interconversion between the conformers.

Molecules 2014, 19
1998
−1
a
Table 5. Relative energies (kcal·mol ) and dihedral angles (°) of transition and ground states .
#
#
#
Structure
∆G (298.15 K)
∆E
∆E
∟C-S-N-C
ZPE
1
1
0.0
3.8
6.7
3.8
0.0
2.3
5.1
0.0
2.4
5.2
84.4
2.0
(
(
1)TS1
1)TS2
179.4
#
∆
Geff
2
2
0.0
3.8
7.0
3.8
0.0
2.5
5.3
0.0
2.4
5.4
84.8
1.7
(
(
2)TS1
2)TS2
179.5
#
∆
Geff
a
#
∆Geff = effective Gibbs free energy of activation.
As mentioned above, an interesting case is found in the structures of ethyl 2-methyl-4-(1-((4-
methylphenyl)sulfonyl)-1H-indol-3-yl)-4-(1-naphthyl)but-2-enoate (Figure 4), for which the
(
E)-isomer 4 crystallizes with two independent molecules in the asymmetric unit, and the (Z)-isomer 3
with only one [15]; in the latter, the experimental structure was artificially manipulated to generate the
other conformer. The conformers for each of 3 and 4 were also optimised. This showed that the
conformers converged to the same energy in the gas-phase for 3 and 4, respectively. Interestingly, the
−1
(
Z)-isomer 3 has an energy 4.1 kcal·mol lower than that calculated for the (E)-isomer 4. An
evaluation of the molecular structures, in particular the intramolecular C-H···O interactions, provides a
clear explanation for the energy difference. Thus, the carbonyl-O atom in (3) forms two significant
−1
C-H···O interactions (–11.9 and –14.6 kcal·mol ) to provide considerable stability to the molecular
structure. In 4, analogous intramolecular C-H···O interactions are also present but these provide
−1
considerably less stabilisation to the molecular structure (−1.8 and −8.7 kcal·mol ).
a–c
Table 6. Occupancies (e) of lone pairs in the transition states according to NBO analyses
.
Orbital
(1)TS1
1.57042
1.99349
1.67855
1.62852
1.99350
1.67817
1.62936
1.99690
1.88105
16.04996
(1)TS2
1.57054
1.99354
1.67991
1.62776
1.99355
1.67999
1.62766
1.99679
1.88124
16.05098
Δn
(2)TS1
1.99357
1.67815
1.6318
(2)TS2
1.99359
1.67935
1.63041
1.99358
1.67935
1.63044
1.58039
Δn
n
N
−0.000120
−0.00005
−0.00136
0.00076
−0.00002
−0.00120
0.00139
n
O1(1)
nO1(2)
nO1(3)
nO2(1)
nO2(2)
nO2(3)
nO3(1)
nO3(2)
Total
1.99356
1.67799
1.63202
1.57986
−0.00002
−0.00136
0.00158
−0.00005
−0.00182
0.00170
−0.00053
0.00011
−0.00019
−0.00102
12.18695
12.18711
−0.00016
a
b
n
O3 refers to the aldehyde-O3 atom which is found only in compound 1; numbers in parenthesis the label
c
of the lone pair; Δn = TS1 − TS2.

Molecules 2014, 19
Table 7. Relative NBO Steric Exchange Energies between oxygen and nitrogen lone pairs.
1999
−
1
−1
Structure ∆Esteric/kcal·mol
Structure ∆Esteric/kcal·mol
1
0.0
0.9
0.8
2
0.0
0.9
0.9
(
(
1)TS1
1)TS2
(2)TS1
(2)TS2
3
. Experimental
.1. General Information
All reagents ware obtained from commercial sources. Melting points were determined on a Büchi
3
B-545 (Büchi Labortechnik AG, Flawil, Switzerland); NMR data were obtained on a Bruker Avance
DPX-300 spectrometer (Bruker BioSpin GmbH, Karlsruhe, Germany).
3.2. Synthesis and Characterization
Into a previously flamed two-necked round-bottomed flask under a nitrogen atmosphere was poured
the 1H-indole-3-carbaldehyde (0.145 g, 1 mmol, 1 eq.), CH Cl (5 mL), TsCl (0.22 g, 1.15 mmol, 1.15 eq.),
2
2
Et
This was followed by vigorous stirring for 2 h at room temperature. The mixture was acidified with a 1 N
HCl solution and extracted with EtOAc, washed with a saturated solution of NH Cl and H O, and
dried under MgSO . The remaining solvent was removed under reduced pressure. The solid was
3
N (0.20 mL, 1.5 mmol, 1.5 eq.) and 4-dimethylaminopyridine (4-DMAP, 0.012 g, 10 mol%, 0.1 eq.).
4
2
4
washed with MeOH three times (yield = 88%). Crystals for X-ray analysis were obtained by slow
1
evaporation from its EtOAc solution held at 293 K; M.p: 420–423 K. NMR H (CDCl
3
, 300 MHz) δ
(
ppm): 10.09 (s, 1H), 8,25 (dd, J = 9.2 and 0.7 Hz, 1H), 7,94 (dd, J = 9.2 and 0.7 Hz, 1H), 7.86 (t,
J = 1.8 Hz 1H), 7.83 (t, J = 1.8 Hz 1H), 7.38 (qtd. J= 15.3, 8.0 and 1.5 Hz, 2H), 7.29 (d, J = 8.0 Hz,
1
3
2
3
H), 7.25 (s, 1H), 2.37 (s, 3H). NMR C (CDCl , 75 MHz) δ (ppm): 185.27, 146.15, 136.17, 135.30,
1
34.48, 130.33 (2C), 127.25 (2C), 126.35, 126.32, 125.07, 122.63, 122.44, 113.29, 21.68.
3
.3. X-ray Data Collection and Processing
Data for a colourless block (0.20 × 0.25 × 0.30 mm) were collected at 100(2)K on an Agilent Super
Nova-Dual diffractometer (Agilent Technologies Inc., Santa Clara, CA, USA) using Cu Kα radiation
mirror monochromator) and an Atlas detector using the  scan technique to θmax = 76.5°. No. of unique
(
data = 5053, No. of parameters = 381, R (4882 data with I ≥ 2σ(I)) = 0.034, wR(all data) = 0.094. The
2
structure was solved by direct methods [17] and refined by full-matrix least-squares on F , with
anisotropic displacement parameters for non-hydrogen atoms. The H atoms were geometrically placed
(
C—H = 0.95–0.98 Å) and refined as riding with Uiso(H) = 1.2–1.5Ueq(C). The weighting scheme used
2
2
2
2
2
2
o o c
was w = 1/[σ (F ) + 0.065P + 0.201P] where P = (F + 2F )/3) with SHELXL-97 [18] on F . The
programs WinGX [19] and ORTEP3 for Windows [19], PLATON [20], MarvinSketch 5.1.10 [21] and
DIAMOND [22] 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 935801. Copies of this information may be

Molecules 2014, 19
2000
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 using the PC GAMESS package with the B3LYP hybrid function,
the STO-3G** basis set and wxMacMolPlt software for structure visualization [23–30]. The
optimization algorithm was based on the Quadratic Approximation (QA) and the threshold gradient
−5
value used was 10 a.u. [31]. Frequency analyses were carried out to verify the nature of the minimum
state of all the stationary points obtained. The Intrinsic Reaction Coordinate (IRC) calculations were
done using the Gonzalez-Schlegel second-order method [32] with the former threshold gradient value
and a step size between points of the reaction path of 0.2 a.u. The NBO donor-acceptor pairs were
checked and second-order stabilization energies were calculated for the interaction studies [33–38].
The crystallographic structures were used as starting point for calculations.
3
.5. CSD Survey Methodology
The Cambridge Structural Database (CSD: 5.32 + 4 updates) [10] was searched using CONQUEST
(Version 1.14) [14] for the structural skeleton shown in Figure 10; structures featuring disorder or
errors were excluded.
Figure 10. Generic 1-(arylsulfonyl)indole structure employed in the CSD search.
4
. Conclusions
Two independent molecules comprise the asymmetric unit of 1-[(4-methylbenzene)sulfonyl]indole-
3
-carbaldehyde (1) which differ in terms of rotation about the central S-N bond; in deuterated
chloroform solution only one conformation was found. DFT calculations show that the molecules
converge to the same energy minimised gas-phase structure, and the IRC analysis shows the energy
−1
barrier to rotation about the S-N bond is ca 3.0 kcal·mol . Comparable energy barriers to rotation
*
were found in related 1-(arylsulfonyl)indole derivatives. The NBO analysis showed that the n
N
→σ S-C
hyperconjugative effects provide stabilization to the S-N bonding the ground state. While -effects do
*
not explain this rotational barrier, three-dimensional n→σ S-X interactions and the increase the
repulsion between lone pairs do.

Molecules 2014, 19
2001
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/2/1990/s1.
Acknowledgments
The Brazilian authors thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
for financial support of this research (grant 2012/00424-2), the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) for scholarships to L.S.M. and S.N.S.V. and fellowships to J.Z.-S.
(
306532/2009-3) and H.A.S. (308320/2010-7), and Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior CAPES (808/2009) to J.Z.-S. E.R.T.T. thanks the Ministry of Higher Education
Malaysia) and the University of Malaya for funding structural studies through the High-Impact
(
Research scheme (UM.C/HIR-MOHE/SC/03). We also acknowledge partial support for the publication
fee by the Institut Pengurusan dan Pemantauan Penyelidikan (IPPP) of the University of Malaya. The
authors thank Ana Cristina Isler of UNICAMP for the NMR measurements.
Author Contributions
Julio Zukerman-Schpector co-responsible for final crystallography, write-up and students
supervisor; Lucas Sousa Madureira responsible for theoretical calculations; Glaudeston Dutra Wulf
co-responsible for final crystallography; Hélio A. Stefani co-responsible for the synthesis,
crystallization and student supervisor; Stanley N. S. Vasconcelos, co-responsible for the synthesis and
crystallization; Seik Weng Ng X-ray responsible for X-ray data collection and initial refinement;
Edward R. T. Tiekink responsible for general write-up and co-responsible for final crystallography.
Conflicts of Interest
The authors declare no conflict of interest.
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2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
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(