Synthesis and crystal structure of [1-(toluene-4-sulfonyl)-piperidin-4-yl]- methanol

Article abstract of DOI:10.1080/15421400801916769

The title compound, [1-(toluene-4-sulfonyl)-piperidin-4-yl]-methanol was synthesized by the condensation of diphenyl(piperidin-4-yl)methanol with p-toluenesulfonyl chloride in methylene dichloromethane as solvent and triethylamine as the base. The product obtained was characterized by spectroscopic techniques and the structure was investigated by X-ray crystallography. The compound crystallizes in the monoclinic crystal class in the space group P21/c with cell parameters a=10.2490(13) A, b=11.4710(9) A, c=20.997(3) A, =116.344(3), V=2212.2(5) A3 for Z=4. The structure reveals that the piperidine ring is in a chair conformation. The geometry around the S atom is comparable with the classic tetrahedral value. The structure exhibits both inter and intramolecular hydrogen bonds of the type O-HO and C-HO.

Full text of DOI:10.1080/15421400801916769

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Synthesis and Crystal Structure
of [1-(Toluene-4-Sulfonyl)-
Piperidin-4-yl]-Methanol
H. R. Girish a , S. Naveen b , S. B. Benaka Prasad a
,
C. S. Ananda Kumar a , K. Vinaya a , M. A. Sridhar b
J. Shashidhara Prasad b & K. S. Rangappa a
,
a Department of Studies in Chemistry , University of
Mysore , Mysore , India
b Department of Studies in Physics , University of
Mysore , Mysore , India
Published online: 31 Aug 2012.
To cite this article: H. R. Girish , S. Naveen , S. B. Benaka Prasad , C. S. Ananda
Kumar , K. Vinaya , M. A. Sridhar , J. Shashidhara Prasad & K. S. Rangappa
(2008) Synthesis and Crystal Structure of [1-(Toluene-4-Sulfonyl)-Piperidin-4-
yl]-Methanol, Molecular Crystals and Liquid Crystals, 487:1, 160-169, DOI:
10.1080/15421400801916769
To link to this article: http://dx.doi.org/10.1080/15421400801916769
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Mol. Cryst. Liq. Cryst., Vol. 487, pp. 160–169, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 1542-1406 print=1563-5287 online
DOI: 10.1080/15421400801916769
Synthesis and Crystal Structure of [1-(Toluene-4-
Sulfonyl)-Piperidin-4-yl]-Methanol
H. R. Girish1, S. Naveen2, S. B. Benaka Prasad1,
C. S. Ananda Kumar1, K. Vinaya1, M. A. Sridhar2,
J. Shashidhara Prasad2, and K. S. Rangappa1
1Department of Studies in Chemistry, University of Mysore, Mysore,
India
2Department of Studies in Physics, University of Mysore, Mysore, India
The title compound, [1-(toluene-4-sulfonyl)-piperidin-4-yl]-methanol was
synthesized by the condensation of diphenyl(piperidin-4-yl)methanol with p-
toluenesulfonyl chloride in methylene dichloromethane as solvent and triethy-
lamine as the base. The product obtained was characterized by spectroscopic
techniques and the structure was investigated by X-ray crystallography. The
compound crystallizes in the monoclinic crystal class in the space group
˚
˚
P21=c with cell parameters a ¼ 10.2490(13) A, b ¼ 11.4710(9) A, c ¼ 20.997(3)
ꢀ
3
˚
˚
A, b ¼ 116.344(3) , V ¼ 2212.2(5) A for Z ¼ 4. The structure reveals that the
piperidine ring is in a chair conformation. The geometry around the S atom
is comparable with the classic tetrahedral value. The structure exhibits both
inter and intramolecular hydrogen bonds of the type OꢁH ꢂꢂꢂ O and CꢁH ꢂꢂꢂ O.
Keywords: chair conformation; hydrogen bonds; toluenesulfonyl chloride
INTRODUCTION
Piperidines are a class of important heterocycles, which exhibits its
diverse therapeutic activities due to its conformationally flexible nat-
ure. Interest in the piperidine class of opiate analgesics continues to
increase in the pharmaceutical community. The biological properties
of these agents have been the subject of on going investigations [1].
The importance of the nitrogen heterocycles, especially piperidine
type, as subunits of bio-active molecules stimulates the chemist for the
Address correspondence to Dr. K. S. Rangappa, Department of Studies in Chemistry,
Manasagangotri, University of Mysore, Mysore 570 006, India. E-mail: rangappaks@
gmail.com
160

Synthesis and Crystal Structure
161
development of new synthetic methods [2]. Thus piperidine derivatives
are associated with diverse pharmacological significance and are thus
considered as privileged scaffolds. Piperidine is a key structural
component of successful anti-Parkinsons drugs [3] and displays anti-
psychotic [4], antiviral [5], metabolic [6], antimicrobial [7], antidepres-
sants [8], acetylcholinesterase inhibitor [9], antimalarial [10], and
anticonvulsant [11,12] properties.
In continuation of our work on the synthesis and characterization
of bioactive heterocycles and their biological evaluation, the title
compound was synthesized. The compound obtained was charac-
terized by spectroscopic techniques and finally confirmed by X-ray
crystallography.
EXPERIMENTAL
Melting points were determined using Veego model VMP-III melting
point apparatus and are uncorrected. Infrared (IR) spectra were
recorded using a Jasco FTIR-4100 series. Nuclear magnetic resonance
(1H NMR) spectra were recorded on a Bruker AM-400 spectrometer
and chemical shifts are expressed in parts per million (ppm, for d) rela-
tive to tetra methyl silane as an internal standard and DMSO-d6 as
solvent. Spin multiplets are given as s (singlet), d (doublet), t (triplet),
q (quartet), and m (multiplet). Elemental (CHNS) analysis was
obtained on Vario EL III Elementar. Silica gel column chromato-
graphy was performed using Merck 7734 silica gel (60–120 mesh)
and Merck made TLC plates. The reaction scheme is shown in Fig. 1.
Synthesis of Diphenyl-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-
methanol
A solution of diphenyl(piperidin-4-yl)methanol 1 (0.5 g, 1.77 mmol), in
dry dichloromethane was taken and cooled to 0–5ꢀC in an ice bath.
Triethylamine (0.537 g, 5.31 mmol) was added to the cold reaction mix-
ture and stirred for 10 minutes. Then p-toluenesulfonyl chloride
(0.338 g, 1.77 mmol) was added and the reaction mixture was stirred
at room temperature for 5 hours. The reaction mixture was monitored
by TLC. Upon completion of the reaction, the solvent was removed
under reduced pressure and the residue was taken in water and
extracted with ethyl acetate. The organic layer was washed with 10%
ammonium chloride solution and finally water wash was given to the
organic layer and dried with anhydrous sodium sulphate. The solvent
was evaporated to get a crude product which was purified by column
chromatography over silica gel (60–120 mesh) using hexane:ethyl

162
H. R. Girish et al.
FIGURE 1 Reaction scheme. (i) p-toluenesulfonyl chloride, TEA, MDC, r. t., 4 hr.
acetate (8:2) as an eluent. The pale brown crystalline solid obtained was
dissolved in ethyl acetate. Pure light brown crystals were obtained after
four days due to the slow evaporation of the solvent. M.P.: 165–167ꢀC,
Yield 90%.
Anal. Calcd. for C25H27NO3S (in %): C: 71.23, H: 6.46, N: 3.32, S:
7.61. Found C: 71.20, H: 6.40, N: 3.28, S: 7.58.
1H NMR (DMSO, 400 MHz): d 7.7 (m, 4H, Ar-H), 7.48 (m, 4H, Ar-H),
7.35 (m, 4H, Ar-H), 7.18 (t, 2H, Ar-H), 3.13 (d, 2H, -CH2), 2.65 (t, 2H,
-CH2), 2.46 (m, 1H, -CH), 2.31 (s, 3H, -CH3), 2.2 (s,1H, -OH), 1.5 (d, 4H,
-CH2).
IR (KBr, cm1): 3500, 2856, 1350, 1276.
MS (ESI) m=z: 422.17 (M þ Hþ).
CRYSTAL STRUCTURE DETERMINATION
A
single crystal of the title compound with dimensions
0.27 ꢁ 0.25 ꢁ 0.25 mm was chosen for an X-ray diffraction study. The
data were collected on a DIPLabo Image Plate system equipped with
a normal focus, 3 kW sealed X-ray source (graphite monochromated
MoKa). The crystal to detector distance is fixed at 120 mm with a
detector area of 441 ꢁ 240 mm2. Thirty six frames of data were col-
lected at room temperature by the oscillation method. Each exposure
of the image plate was set to a period of 400s. Successive frames were

Synthesis and Crystal Structure
163
scanned in steps of 5ꢀ per minute with an oscillation range of 5ꢀ. Image
processing and data reduction were done using Denzo [13]. The reflec-
tions were merged with Scalepack [14]. All of the frames could be
indexed using a primitive monoclinic lattice. Absorption correction
was not applied. The structure was solved by direct methods using
SHELXS-97 [15]. Least-squares refinement using SHELXL-97 [16]
with isotropic temperature factors for all the non-hydrogen atoms con-
verged the residual R1 to 0.1413. Subsequent refinements were car-
ried out with anisotropic thermal parameters for non-hydrogen
atoms and isotropic temperature factors for the hydrogen atoms which
were placed at chemically acceptable positions. The hydrogen atoms
were allowed to ride on their parent atoms. After eight cycles of refine-
ment the residual converged to 0.0452. The details of crystal data and
TABLE 1 Crystal Data and Structure Refinement Table
CCDC Deposition Number
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
CCDC 667632
25H27NO3S
421.54
C
293(2)K
˚
0.7I073 A
Monoclinic
P21=c
˚
Cell dimensions
a ¼ 10.2490(13) A
˚
b ¼ 11.4710(9) A
˚
c ¼ 20.997(3)A
b ¼ 116.344(3)ꢀ
3
˚
Volume
2212.2(5) A
Z
4
Density (calculated)
Absorption coefficient
F000
1.266 Mg=m3
0.172 mmꢂ1
896
Crystal size
Theta range for data collection
Index ranges
0.27 ꢁ 0.25 ꢁ 0.25 mm
2.31ꢀ to 25.02ꢀ
ꢂ11 ꢃ h ꢃ 11
ꢂ11 ꢃ k ꢃ 11
ꢂ24 ꢃ l ꢃ 24
4241
Reflections collected
Independent reflections
Absorption correction
Refinement method
Data=restraints=parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
2460 [R(int) ¼ 0.0211]
None
Full-matrix least-squares on F2
2460=0 =273
1.108
R1 ¼ 0.0452, wR2 ¼ 0.1311
R1 ¼ 0.0574, wR2 ¼ 0.1504
0.014(3)
Extinction coefficient
Largest diff. peak and hole
ꢂ3
˚
0.158 and ꢂ0.234 eꢄA

164
H. R. Girish et al.
TABLE 2 Atomic Coordinates and Equivalent Thermal Parameters of the
Non-hydrogen Atoms
Atom
x
y
z
Ueq
N1
C2
C3
C4
C5
C6
S7
O8
0.5554(3)
0.6723(4)
0.7464(4)
0.8075(4)
0.6883(4)
0.6082(5)
0.4046(1)
0.3856(3)
0.2939(3)
0.4206(4)
0.3261(5)
0.3332(6)
0.4339(4)
0.5306(4)
0.5243(4)
0.4380(7)
0.8826(4)
0.7735(3)
0.9960(4)
1.1184(4)
1.2158(5)
1.1961(5)
1.0779(5)
0.9803(4)
0.9522(4)
0.9450(5)
1.0088(6)
1.0817(6)
1.0917(6)
1.0286(5)
ꢂ0.0314(2)
ꢂ0.0317(2)
ꢂ0.1500(2)
ꢂ0.1780(2)
ꢂ0.1660(2)
ꢂ0.0489(3)
0.03678(6)
0.0461(2)
0.1744(2)
0.2474(2)
0.2626(2)
0.2099(2)
0.1339(2)
0.1202(2)
0.15233(5)
0.2160(1)
0.0916(2)
0.1262(2)
0.0603(2)
0.0417(3)
0.0885(2)
0.1538(2)
0.1734(2)
0.0697(3)
0.2237(2)
0.2063(1)
0.3009(2)
0.3297(2)
0.4006(2)
0.4459(2)
0.4181(2)
0.3474(2)
0.1731(2)
0.1438(2)
0.0989(2)
0.0832(2)
0.1119(3)
0.1568(2)
0.0551(8)
0.0530(8)
0.0503(8)
0.0469(8)
0.0551(9)
0.0582(9)
0.0529(3)
0.0698(8)
0.0735(8)
0.0475(7)
0.0727(1)
0.0851(2)
0.0621(9)
0.0606(9)
0.0597(9)
0.0961(2)
0.0464(8)
0.0564(6)
0.0476(8)
0.0595(9)
0.0693(1)
0.0712(1)
0.0761(1)
0.0626(9)
0.0507(8)
0.0591(9)
0.0778(1)
0.0837(1)
0.0831(1)
0.0692(1)
O9
ꢂ0.0201(2)
C10
C11
C12
C13
C14
C15
C16
C17
O18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
0.1792(2)
0.2180(3)
0.3340(3)
0.4093(3)
0.3674(3)
0.2539(3)
0.5366(3)
ꢂ0.2998(2)
ꢂ0.3886(2)
ꢂ0.3115(2)
ꢂ0.2401(3)
ꢂ0.2451(3)
ꢂ0.3218(3)
ꢂ0.3948(3)
ꢂ0.3912(3)
ꢂ0.3221(2)
ꢂ0.4311(3)
ꢂ0.4531(4)
ꢂ0.3673(4)
ꢂ0.2593(4)
ꢂ0.2364(3)
P P
Ueq ¼ ð1=3Þ
j Uijðaꢅi aꢅj Þðai ꢄ ajÞ:
i
refinement are given in Table 1.y Table 2 gives the atomic coordinates
and equivalent thermal parameters of the non-hydrogen atoms.
Tables 3 and 4 give the list of bond lengths and bond angles respect-
ively which are in good agreement with the standard values.
The ORTEP of the molecule with thermal ellipsoids drawn at 50%
probability is shown in Fig. 2.
yCCDC 667632 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; Fax: +44(0)1223-336033. E-mail: de-posit@ccdc.cam.ac.uk

Synthesis and Crystal Structure
165
˚
TABLE 3 Bond Lengths (A)
Atoms
Length
Atoms
Length
N1-C2
N1-C6
N1-S7
C2-C3
C3-C4
C4-C5
C4-C17
C5-C6
S7-O9
1.469(5)
1.475(3)
1.605(3)
1.519(4)
1.528(3)
1.526(5)
1.558(4)
1.533(4)
1.434(3)
1.438(2)
1.754(3)
1.365(5)
1.382(5)
1.397(5)
1.371(6)
1.373(6)
1.518(5)
C14-C15
C17-O18
C17-C19
C17-C25
C19-C20
C19-C24
C20-C21
C21-C22
C22-C23
C23-C24
C25-C26
C25-C30
C26-C27
C27-C28
C28-C29
C29-C30
1.376(4)
1.435(3)
1.525(5)
1.540(3)
1.392(5)
1.398(4)
1.377(6)
1.375(5)
1.372(6)
1.374(6)
1.381(4)
1.390(4)
1.388(4)
1.362(6)
1.361(6)
1.386(4)
S7-O8
S7-C10
C10-C11
C10-C15
C11-C12
C12-C13
C13-C14
C13-C16
TABLE 4 Bond Angles (ꢀ)
Atoms
Angle
Atoms
Angle
C2-N1-C6
C2-N1-S7
C6-N1-S7
N1-C2-C3
C2-C3-C4
C5-C4-C3
C5-C4-C17
C3-C4-C17
C4-C5-C6
N1-C6-C5
O9-S7-O8
O9-S7-N1
O8-S7-N1
O9-S7-C10
O8-S7-C10
N1-S7-C10
C11-C10-C15
C11-C10-S7
C15-C10-S7
C10-C11-C12
C13-C12-C11
C12-C13-C14
C12-C13-C16
C14-C13-C16
113.4(3)
122.5(2)
118.7(2)
108.7(2)
111.3(2)
110.0(2)
112.0(2)
112.4(2)
112.9(3)
108.9(2)
118.6(2)
108.4(1)
106.1(1)
107.1(2)
106.9(1)
109.5(1)
119.9(3)
119.9(3)
120.1(3)
119.5(4)
121.1(5)
118.4(3)
121.2(4)
120.4(4)
C13-C14-C15
C14-C15-C10
O18-C17-C19
O18-C17-C25
C19-C17-C25
O18-C17-C4
C19-C17-C4
C25-C17-C4
C20-C19-C24
C20-C19-C17
C24-C19-C17
C21-C20-C19
C22-C21-C20
C23-C22-C21
C22-C23-C24
C23-C24-C19
C26-C25-C30
C26-C25-C17
C30-C25-C17
C25-C26-C27
C28-C27-C26
C29-C28-C27
C28-C29-C30
C29-C30-C25
121.4(4)
119.7(4)
110.4(2)
104.7(2)
110.5(2)
108.9(2)
110.9(2)
111.2(2)
116.3(3)
121.6(2)
122.0(3)
121.7(3)
121.1(4)
117.9(4)
121.6(3)
121.3(3)
117.0(3)
120.6(2)
122.4(2)
121.3(3)
120.5(3)
119.5(3)
120.5(3)
121.2(3)

166
H. R. Girish et al.
FIGURE 2 ORTEP of the molecule with thermal ellipsoids drawn at 50%
probability.
A study of the torsion angles, asymmetric parameters and least-
squares plane calculations reveals that the piperidine ring in the
structure is in a chair conformation with the atoms N1 and C4 deviat-
˚
˚
ing 0.253(4) A and ꢀ 0.211(4) A from the Cremer and Pople plane [17]
defined by the atoms C2=C3=C5=C6. This is confirmed by the pucker-
ꢁ
ꢁ
˚
ing parameters Q ¼ 0.5701(40) A h ¼ 4.55(40) and U ¼ 40(5) . The
bonds N1-S7 and C4–C17 make an angle of 74.41(11)ꢁ and 71.0(2)ꢁ,
respectively, with the Cremer and Pople plane of the piperidine ring
and thus lie in the equatorial plane of the piperidine ring. The
dihedral angle between the least-squares plane of the piperidine ring
and the phenyl ring C19–C24 is 89.40(19)ꢁ implying that the phenyl
ring is nearly perpendicular to the plane of the piperidine ring. The
other phenyl ring C25–C30 makes a dihedral angle of 73.4(2)ꢁ with
the least-squares plane of the piperidine ring. The dihedral angle
between the two phenyl rings bridged by the alcoholic group is
65.9(2)ꢁ. The methylphenyl ring is inclined at an angle of 66.3(2)ꢁ to
the sulfonyl plane. The sulfonyl O atoms O8 and O9 are oriented in
þsynperiplanar and ꢀsynclinal conformations as indicated by the
torsion angle values of ꢀ24.8(3)ꢁ and 54.6(3)ꢁ for C2-N1-S7-O8 and
C6-N1-S7-O9, respectively.
The geometry around the S atom is distorted tetrahedron, with the
largest deviations observed for the O-S-O [O8-S7-O9 ¼ 118.6(2)ꢁ] and
O-S-N angles [O9 S7 Nl ¼ 108.4(l)ꢁ. This widening of angles is due
to the repulsive interaction between the two short S¼O bonds.

Synthesis and Crystal Structure
167
FIGURE 3 Packing of the molecules when viewed down the a axis. The
dashed lines indicate the hydrogen bonds.
˚
The S-N bond distance lies within the expected range of 1.60–1.69 A.
The bond angle for N1-S7-C10 ¼ 109.5(1)ꢀ is comparable with the clas-
sic tetrahedral value of 109.47ꢀ. Similar conformation was observed in
the molecule of [1-(4-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-
diphenyl-methanol [18]. The structure exhibits both inter and intra-
molecular hydrogen bonds of the type O-H ꢄꢄꢄ O and C-H ꢄꢄꢄ O. The
intermolecular hydrogen bond O18-H18 ꢄꢄꢄ O8 between the alcoholic
˚
group and the sulfonyl group has a length of 2.871(4) A and an angle
of 151ꢀ with the symmetry code 1 – x, ꢂ1=2 þ y, 1=2 – z while the other
hydrogen bond C14-H14 ꢄꢄꢄ O8 hydrogen bond between the methylphenyl
˚
ring and the sulfonyl group has a length of 3.214(4) A and an angle
of 133ꢀ with the symmetry code ꢂ1 þ x, 1=2 þ y, 1=2 – z. The packing

168
H. R. Girish et al.
of the molecules when viewed down the a axis indicate that the molecules
are stacked in pairs and they form a one dimensional polymeric chain
(Fig. 3).
ACKNOWLEDGMENTS
The authors are grateful to Department of Science and Technology and
Government of India for financial assistance under the projects SP=
I2=FOO=93 and UGC-SAP(Phase-I)No. F.540=10=DRS=2004(S AP-I).
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