Synthesis and crystal structure of 1-(cyano(4-methoxyphenyl)methyl) cyclohexyl acetate

Article abstract of DOI:10.1080/15421400701432404

The title compound, C17H21NO3, was synthesized by the acetylation of the hydroxy group of 1-(cyano(4-methoxyphenyl)methyl)cyclohexanol, which was formed by the reaction of 4-methoxyphenyl acetonitrile with cyclohexanone. The compound was characterized spectroscopically, and the structure was investigated by X-ray crystallography. The compound crystallizes in the orthorhombic crystal class in the space group Pbca with cell parameters a = 13.412(6) A, b = 12.398(14) A, c = 19.026(19) A and V = 3164(5) A³ for Z = 8. The cyclohexane ring is in a chair conformation. The structure exhibits intermolecular hydrogen bonds of the type C-H....N and C-H....O. Copyright Taylor & Francis Group, LLC.

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Synthesis and Crystal
Structure of 1-(Cyano(4-
methoxyphenyl)methyl)cyclohexyl
Acetate
K. Mantelingu a , C. V. Kavitha a , K. S. Rangappa a
,
S. Naveen b , M. A. Sridhar b & J. Shashidhara Prasad
b
a Department of Studies in Chemistry , University of
Mysore , Mysore, India
b Department of Studies in Chemistry , University of
Mysore , Mysore, India
Published online: 22 Sep 2010.
To cite this article: K. Mantelingu , C. V. Kavitha , K. S. Rangappa , S. Naveen , M. A.
Sridhar & J. Shashidhara Prasad (2007) Synthesis and Crystal Structure of 1-(Cyano(4-
methoxyphenyl)methyl)cyclohexyl Acetate, Molecular Crystals and Liquid Crystals,
469:1, 121-129, DOI: 10.1080/15421400701432404
To link to this article: http://dx.doi.org/10.1080/15421400701432404
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Mol. Cryst. Liq. Cryst., Vol. 469, pp. 121–129, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 1542-1406 print=1563-5287 online
DOI: 10.1080/15421400701432404
Synthesis and Crystal Structure of 1-(Cyano-
(4-methoxyphenyl)methyl)cyclohexyl Acetate
K. Mantelingu
C. V. Kavitha
K. S. Rangappa
Department of Studies in Chemistry, University of Mysore,
Mysore, India
S. Naveen
M. A. Sridhar
J. Shashidhara Prasad
Department of Studies in Physics, University of Mysore,
Mysore, India
The title compound, C17H21NO3, was synthesized by the acetylation of the hydroxy
group of 1-(cyano(4-methoxyphenyl)methyl)cyclohexanol, which was formed by the
reaction of 4-methoxyphenyl acetonitrile with cyclohexanone. The compound was
characterized spectroscopically, and the structure was investigated by X-ray crys-
tallography. The compound crystallizes in the orthorhombic crystal class in the
˚
˚
space group Pbca with cell parameters a ¼ 13.412(6) A, b ¼ 12.398(14) A,
c ¼ 19.026(19) A, and V ¼ 3164(5) A3 for Z ¼ 8. The cyclohexane ring is in a chair
conformation. The structure exhibits intermolecular hydrogen bonds of the type
C–Hꢀ ꢀ ꢀN and C–Hꢀ ꢀ ꢀO.
˚
˚
Keywords: chair conformation; hydrogen bond; venlafaxine
INTRODUCTION
Venlafaxine [1,2] is a new generation antidepression drug, quite
different from other antidepressants, with a unique structure and
morphological effects. Cycloalkanols serve as important intermediates
for the synthesis of potent drugs such as venlafaxine. In addition, the
use of the nitrile function for CꢁC bond-formation reaction occupies an
Address correspondence to K. S. Rangappa, Department of Studies in Chemistry,
Manasagangotri, University of Mysore, Mysore, India. E-mail: rangappaks@chemistry.
uni-mysore.ac.in
121

122
K. Mantelingu et al.
important position in organic chemistry [3,4]. Particularly, deprotona-
tion of the a-carbon and alkylation are important reactions [5]. The
nitrile group undergoes reduction with many reducing agents.
Depending on the nature of the reducing agent and experimental con-
ditions, the reaction can produce amines, aldehydes, primary alcohols,
imines, or alkanes [6,7]. In pursuit of the methods for synthesis of
analogs of the key intermediate, 1-(cyano-(4-methoxyphenyl)methyl)-
cyclohexanol, we have synthesized the title compound under mild con-
ditions. This protocol can be successfully employed for the synthesis of
a wide variety of other natural products and commercially important
pharmaceuticals [8]. The present study was undertaken to study the
structural conformation of the title compound, and herein we report
the synthesis and crystal structure of 1-(cyano(4-methoxyphenyl)-
methyl)cyclohexyl acetate.
EXPERIMENTAL
The melting point was recorded on a Selaco-650 hot-stage apparatus and
is uncorrected. The IR (KBr) spectra was recorded on a Jasco FT=IR-4100
Fourier transform infrared (FTIR) spectrometer. 1H NMR spectra were
recorded on a Shimadzu AMX 400 spectrometer using CDCl3 as solvent
and TMS as an internal standard (chemical shifts in ppm). Elemental
analysis was done on a Vario-EL instrument. Thin-layer chromato-
graphy (TLC) was conducted on 0.25-mm silica-gel plates (60F254
,
Merck); visualization was made with ultraviolet (uv) light. All the
extracted solvents were dried over anhydrous Na2SO4 and evaporated
with a Buchi rotary evaporator. The reagents were obtained commer-
cially and were used as received. The reaction scheme is shown in Fig. 1.
Synthesis of 1-(Cyano-(4-methoxyphenyl)methyl)cyclohexanol
To a magnetically stirred solution of sodium hydroxide (20 g, 0.5 mol)
in methanolic water at 0ꢂC, a mixture of 4-methoxyphenyl acetonitrile
(50 g, 0.340 mol) was added, and cyclohexanone (49.9 g, 0.515 mol) was
dissolved in methanol slowly, followed by the addition of tetrabutyl
ammonium hydrogen sulfate (5 g). The reaction mass was stirred for
6 h at room temperature (25–30ꢂC) and filtered. The residue was thor-
oughly washed with water (500 ml) and hexane (200 ml) to obtain the
compound (82 g, 98%).
Mp: 122–124ꢂC. Anal. calcd. for C15H19NO2: C, 73.44; H, 7.81; N,
1
5.71. Found: C, 73.43; H, 7.80; N, 5.72. H NMR (CDCl3, 300 MHz):
d 7.30 (d, 2H, Ar-H), 6.91 (d, 2H, Ar-H), 3.81 (s, 3H, OCH3), 3.75 (s,
1H, OH), 1.55 (m, 10H, cyclohexyl).

Synthesis and Crystal Structure
123
FIGURE 1 Reaction Scheme.
Synthesis of 1-(Cyano(4-methoxyphenyl)methyl)cyclohexyl
Acetate
1-(Cyano(4-methoxyphenyl)methyl)cyclohexanol was dissolved in
dichloromethane followed by the addition of acetic anhydride (2.3 ml,
1.5 eq) and zinc chloride (5.56 g, 2 eq). The reaction mixture was
refluxed at 45–55ꢂC for about 3 h. After completion of the reaction,

124
K. Mantelingu et al.
the reaction mixture was quenched with water and extracted with
dichloromethane (2 ꢃ 50 ml). The combined organic layer was evapo-
rated under reduced pressure. Pure colorless crystals were obtained
by the slow evaporation of ethyl acetate.
Mp: 122–124ꢂC. Anal. calcd. for C17H21NO3: C, 71.06; H, 7.37; N,
1
4.87. Found: C, 71.05; H, 7.37; N, 4.88. H NMR (CDCl3, 300 MHz):
d 7.30 (d, 2H, Ar-H), 6.91 (d, 2H, Ar-H), 3.81 (s, 3H, ꢁOCH3), 2.12
(s, 3H, ꢁCH3), 5.01 (s, 1H, ꢁCHꢁCN), 1.55 (m, 10H, cyclohexyl).
CRYSTAL STRUCTURE DETERMINATION
A single crystal of the title compound with dimensions 0.27 ꢃ 0.25 ꢃ
0.2 mm was chosen for an X-ray diffraction study. The data were
TABLE 1 Crystal Data and Structure Refinement
Parameter
Value
CCDC deposition number
Empirical formula
Formula weight
Temperature
CCDC 616861
C17H21NO3
287.35
293(2) K
0.71073 A
˚
Wavelength
Crystal system
Space group
Cell dimensions
Orthorhombic
Pbca
˚
a ¼ 13.412(6) A
˚
˚
b ¼ 12.398(14) A
c ¼ 19.026(19) A
3
˚
Volume
3164(5) A
Z
8
Density(calculated)
Absorption coefficient
F000
1.207 Mg=m3
0.082 mm ꢁ 1
1232
Crystal size
Theta range for data collection
Index ranges
0.27 ꢃ 0.25 ꢃ 0.2 mm
2.14ꢂ to 25.03ꢂ
ꢁ15 ꢄ h ꢄ 15
ꢁ13 ꢄ k ꢄ 13
ꢁ22 ꢄ l ꢄ 22
Reflections collected
4733
Independent reflections
Absorption correction
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
2583 [R(int) ¼ 0.0171]
None
Full-matrix least squares on F2
2583=0=193
1.042
R1 ¼ 0.0740, wR2 ¼ 0.2088
R1 ¼ 0.0993, wR2 ¼ 0.2491
0.029(5)
Extinction coefficient
Largest diff. peak and hole
ꢁ3
˚
0.515 and ꢁ0.389 e.A

Synthesis and Crystal Structure
125
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 ꢃ 240 mm2. Thirty-six frames of data were collected
at room temperature by the oscillation method. Each exposure of
the image plate was set to a period of 400 s. Successive frames were
scanned in steps of 5ꢂ per minute with an oscillation range of 5ꢂ. Image
processing and data reduction were done using Denzo [9]. The reflec-
tions were merged with Scalepack [10]. All of the frames could be
indexed using a primitive orthorhombic lattice. Absorption correction
was not applied. The structure was solved by direct methods using
SHELXS-97 [11]. Least-squares refinement using SHELXL-97 [12]
with isotropic temperature factors for all the nonhydrogen atoms
converged the residual R1 to 0.1677. Subsequent refinements were
carried out with anisotropic thermal parameters for nonhydrogen
atoms and isotropic temperature factors for the hydrogen atoms,
which were placed at chemically acceptable positions. The hydrogen
TABLE 2 Atomic Coordinates and Equivalent Thermal Parameters of the
Nonhydrogen Atoms
Atom
x
y
z
Ueq
C1
C2
C3
C4
C5
C6
O7
C8
0.0381(2)
0.0812(2)
0.1076(3)
0.2824(2)
0.1882(2)
0.2184(2)
0.2654(2)
0.3620(2)
0.3336(2)
0.3715(2)
0.3587(2)
0.2757(2)
0.4599(2)
0.2474(2)
0.1559(2)
0.0864(2)
0.3357(2)
0.3682(2)
0.4506(2)
0.5018(2)
0.4681(2)
0.3865(2)
0.5853(2)
0.6279(3)
0.4711(2)
0.5130(2)
0.5885(2)
0.6267(2)
0.5871(2)
0.5113(2)
0.46489(9)
0.4370(2)
0.4109(2)
0.4421(2)
0.3947(2)
0.3982(2)
0.3991(2)
0.3480(2)
0.3537(2)
0.3132(2)
0.2646(2)
0.2569(2)
0.2983(2)
0.2224(2)
0.2344(2)
0.0568(7)
0.0734(8)
0.0832(1)
0.0800(9)
0.0699(8)
0.0582(7)
0.0596(6)
0.0682(8)
0.0953(8)
0.0846(1)
0.0605(7)
0.0693(8)
0.0902(9)
0.0590(7)
0.0684(8)
0.0710(8)
0.0663(8)
0.0716(8)
0.0669(8)
0.0840(7)
0.0980(2)
0.0194(3)
ꢁ0.0212(2)
ꢁ0.0481(2)
0.1097(2)
0.2001(2)
0.2306(2)
O9
C10
C11
C12
N13
C14
C15
C16
C17
C18
C19
O20
C21
0.2605(2)
0.0080(2)
ꢁ0.0624(2)
ꢁ0.1178(2)
ꢁ0.0347(2)
ꢁ0.1333(2)
ꢁ0.1723(2)
ꢁ0.1114(2)
ꢁ0.0132(2)
0.0240(2)
ꢁ0.1422(2)
ꢁ0.2389(3)
P P
Note.Ueq ¼ ð1=3Þ
Uijðaꢅi aꢅj Þðai ꢀ ajÞ:
i
j

126
K. Mantelingu et al.
˚
TABLE 3 Bond Lengths (A)
Atoms
Length
C1–O7
C1–C6
C1–C2
C1–C11
C2–C3
C3–C4
C4–C5
C5–C6
O7–C8
1.469(3)
1.523(4)
1.528(3)
1.569(4)
1.526(4)
1.505(5)
1.516(4)
1.528(4)
1.334(3)
1.214(3)
1.496(4)
1.477(4)
1.522(4)
1.138(3)
1.383(4)
1.387(4)
1.383(4)
1.387(4)
1.373(3)
1.389(4)
1.376(4)
1.419(4)
C8–O9
C8–C10
C11–C12
C11–C14
C12–N13
C14–C19
C14–C15
C15–C16
C16–C17
C17–O20
C17–C18
C18–C19
O20–C21
atoms were allowed to ride on their parent atoms. After eight cycles of
refinement, the residual converged to 0.0740. The details of crystal
y
data and refinement are given in Table 1. Table 2 gives the atomic
coordinates and equivalent thermal parameters of the nonhydrogen
atoms. Tables 3 and 4 give the list of bond lengths and bond angles
respectively, 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.
The dihedral angle between the cyclohexane ring and the methoxy
phenyl ring is 50.63(15)ꢂ. The methylester group is almost perpendicu-
lar to the cyclohexane ring as indicated by the dihedral angle value of
89.4(2)ꢂ. A study of torsion angles, asymmetric parameters, and least-
squares plane calculations reveal that the cyclohexane ring is in a
chair conformation. This is confirmed by the puckering parameters
ꢂ
ꢂ
˚
Q ¼ 0.5510(35) A, h ¼ 2.94(36) , and / ¼ 170(7) . The bond C1–O7 lies
yCCDC 616861 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: þ44(0)1223-336033; e-mail: deposit@ccdc.cam.ac.uk’).

Synthesis and Crystal Structure
TABLE 4 Bond Angles (ꢂ)
127
Atoms
Angle
O7–C1–C6
O7–C1–C2
C6–C1–C2
O7–C1–C11
C6–C1–C11
C2–C1–C11
C3–C2–C1
C4–C3–C2
C3–C4–C5
C4–C5–C6
C1–C6–C5
C8–O7–C1
O9–C8–O7
O9–C8–C10
O7–C8–C10
C12–C11–C14
C12–C11–C1
C14–C11–C1
N13–C12–C11
C19–C14–C15
C19–C14–C11
C15–C14–C11
C16–C15–C14
C15–C16–C17
O20–C17–C16
O20–C17–C18
C16–C17–C18
C19–C18–C17
C18–C19–C14
C17–O20–C21
102.8(2)
111.6(2)
110.1(2)
107.6(2)
112.7(2)
111.7(2)
113.1(2)
111.6(3)
110.4(3)
111.8(2)
113.1(2)
122.5(2)
124.7(3)
123.8(3)
111.5(2)
109.8(2)
109.6(2)
116.0(2)
178.1(3)
117.6(3)
120.9(3)
121.5(2)
122.2(3)
119.1(3)
123.8(3)
116.7(2)
119.4(3)
120.3(3)
121.4(3)
117.5(2)
in the axial plane of the cyclohexane ring with an angle of 5.48(19)ꢂ
from the Cremer and Pople [13] plane, whereas the bond C1–C11 lies
in the equatorial plane with an angle of 70.2(2)ꢂ. The methoxy group
lies in the plane of the phenyl ring as indicated by the torsion angle
value of 6.4(5)ꢂ for C21–O20–C17–C16. The carbonyl group at C8 is
in the syn-periplanar conformation as indicated by the torsion angle
value of 4.1(5)ꢂ for C1–O7–C8–C9. The acrylonitrile group is in an
anti-periplanar conformation with respect to the C1–C11 bond as
indicated by the torsion angle value of 151.3(1)ꢂ for C1–C11–C12–
N13. The molecule possesses a chiral center at C11. Because the title
compound has crystallized in a centrosymmetric space group, we can
surmise that the material is a racemic mixture. The structure exhibits

128
K. Mantelingu et al.
FIGURE 2 ORTEP of the molecule at 50% probability.
FIGURE 3 Packing of the molecules down the b axis. The dashed lines
represent the hydrogen bonds.

Synthesis and Crystal Structure
129
intermolecular hydrogen bonds of the type C–Hꢀ ꢀ ꢀN and C-Hꢀ ꢀ ꢀO. The
intermolecular hydrogen bonds are C10–H10Aꢀ ꢀ ꢀN13, which has a
ꢂ
˚
length of 3.482(6) A with an angle of 157(2) , and C21–H21Bꢀ ꢀ ꢀO9,
which has a length of 3.319(6)ꢂ and an angle of 152(1)ꢂ, with symmetry
codes 1=2 þ x, 1=2 ꢁ y, 1 ꢁ z, and ꢁx, 1=2 þ y, 1=2 ꢁ z, respectively.
The stability of the crystal structure can be accounted for by these
hydrogen bonds. The packing of the molecules as shown in Fig. 3 indi-
cates that the molecules are interlinked by the hydrogen bonds to form
an infinite chain when viewed down the b axis.
ACKNOWLEDGMENTS
The authors express their thanks to Department of Science and
Technology, Government of India, for financial assistance under
Projects SR=SO=HS-58=2003 and SP=I2=FOO=93.
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