Synthesis, characterization and hirshfeld surface analysis of a 2-thiophene acetic acid derivative

Article abstract of DOI:10.1080/15421406.2014.928978

N,N′-dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide (C₁₉H₂₈N₂ O₂S), was prepared using 1,3-dicyclohexylurea. The compound has been characterized by IR, and single-crystal X-ray diffraction followed by a detailed Hirshfeld surface analysis. The compound crystallizes in the monoclinic space group P₂₁/c, with cell parameters a = 9.0969(3) ?, b = 18.3067(5) ?, c = 11.6499(3) ?, β = 103.876(2)°, V = 1883.49(10) ?³, Z = 4. The crystal structure of the compound is stabilized by the intermolecular interactions of types N-H?O, C-H?O and intramolecular interactions of the type C-H?O.

Full text of DOI:10.1080/15421406.2014.928978

Mol. Cryst. Liq. Cryst., Vol. 607: pp. 223–231, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2014.928978
Synthesis, Characterization and Hirshfeld Surface
Analysis of a 2-thiophene Acetic Acid Derivative
N. LATHA RANI,1 M. P. CHAKRAVARTHY,2 K. N. MOHANA,2
N. K. LOKANATH,1 AND M. A. SRIDHAR1,∗
1Department of Studies in Physics, University of Mysore, Manasagangotri,
Mysore, India
2Department of Studies in Chemistry, University of Mysore, Manasagangotri,
Mysore, India
N,Nꢀ-dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide (C19H28N2 O2S), was pre-
pared using 1,3-dicyclohexylurea. The compound has been characterized by IR, and
single-crystal X-ray diffraction followed by a detailed Hirshfeld surface analysis. The
compound crystallizes in the monoclinic space group P21/c, with cell parameters a =
9.0969(3) Å, b = 18.3067(5) Å, c = 11.6499(3) Å, β = 103.876(2)◦, V = 1883.49(10)
Å3, Z = 4. The crystal structure of the compound is stabilized by the intermolecular
interactions of types N–H . . . O, C–H . . . O and intramolecular interactions of the type
C–H . . . O.
Keywords 2-thiophene acetic acid; Candida albicans; fingerprint plots; FTIR spec-
trum; Hirshfeld surface analysis
Introduction
Organic compounds containing five-membered aromatic heterocyclic rings are widely
distributed in nature and often play an important role in various biochemical pro-
cesses [1]. Thiophene is one such heterocyclic compound. The compound N,Nꢀ-
dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide is derived from 2-thiophene acetic
acid.
Derivatives of 2-thiophene acetic acid have gained remarkable importance due to
their widespread biological activities. For example, thioureides (derived from 2-thiophene
acetic acid) show antifungal activity [2]. Investigations were carried out to determine their
antimicrobial activity. They proved to be active on fungus Candida albicans [3].
In this paper, we report the synthesis and structure analysis of N,Nꢀ-
dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide using FT-IR and single crystal X-ray
diffraction. Intermolecular contacts are studied using Hirshfeld surface analysis.
∗Address correspondence to M. A. Sridhar, Department of Studies in Physics, University of
Mysore, Manasagangotri, Mysore- 570 006, India. Tel.: 0821-2419333, Fax: 0821-2419333; E-mail:
mas@physics.uni-mysore.ac.in
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/gmcl.
223

224
N. Latha Rani et al
Experimental
Synthesis and Crystal Growth
1,3-dicyclohexylurea (C13H24N2O, Mol. Wt. 224.34 g) was synthesized by dissolving 1.43 g
(10 mmol, C7H13NO2, Mol. Wt. 143.18 g) of cyclohexylcarbamic acid and 0.99 g (10 mmol,
C6H13N, Mol. Wt. 99.17 g) of cyclohexanamine in 15 mL DCM (dichloromethane, CH2Cl2,
Mol. Wt. 84.93 g) taken in a round bottom flask. A 4.12 g (20 mmol, C13H22N2, Mol. Wt.
206.33 g) of DCC (N,Nꢀ-Dicyclohexylcarbodiimide) was added and the reaction mixture
was refluxed for 8 h at room temperature in basic condition with the addition of 4 mL
(30 mmol, C6H15N) of triethylamine. The solution obtained was filtered off and the filtrate
was kept for drying at room temperature to get 1,3-dicyclohexylurea.
Later 1.1 g of the obtained 1,3-dicyclohexylurea (5 mmol, C13H24N2O, Mol. Wt.
224.34 g) along with 15 mL of DCM was taken in a clean round bottom flask. To the
resultant mixture 0.71 g (5 mmol, C6H6O2S, Mol. Wt. 142.18 g) of 2-thiopheneacetic acid
in 15 mL DCM was added. To this mixture 2.6 g (10 mmol, C13H22N2, Mol. Wt. 206.33 g)
of DCC was added and the reaction mixture was refluxed for 8 h at room temperature
in basic condition with the addition of 2 mL (15 mmol, C6H15N) of triethylamine. The
solution obtained was filtered off and the filtrate was kept for drying at room temperature to
get N,Nꢀ-dicyclohexylcarbamoyl-2-(thiophen-2-yl) acetamide. Single crystals suitable for
X-ray diffraction study were obtained by a slow evaporation technique using methanol as
a solvent.
Scheme 1. Scheme of N,Nꢀ-dicyclohexylcarbamoyl-2-(thiophen-2-yl)acetamide.
Results and Discussion
FT-IR Spectral Analysis
Infrared spectra were recorded on a Perkin-Elmer spectrophotometer in the range
400–4000 cm−1. The FT-IR spectrum of the crystal structure is shown in Fig. 1. The
peak at 3386 cm−1 is due to N–H stretching vibrations. The peaks observed at 1690 cm−1
and 1649 cm−1 correspond to C O stretching. The peaks at 1452 cm−1 and 675 cm−1 are
due to C–N and C–S stretching vibrations, respectively.
Single Crystal X-ray Diffraction
A yellow colored, prismatic single crystal of the synthesized compound with approximate
dimensions of 0.23 × 0.22 × 0.21 mm was used for X-ray diffraction study. Data were
collected on a Bruker CCD diffractometer equipped with Cu Kα radiation. Data reduction

Synthesis, Characterization, and Hirshfeld Surface Analysis
225
Figure 1. The FT-IR spectrum of the crystal structure.
Table 1. Crystal data and details of the structure determination
CCDC deposition number
Formula
Formula weight
Crystal system
Space group
988475
C19H28N2O2S
348.50
Monoclinic
P21/c
Unit cell dimensions
a = 9.0969(3) Å,
b = 18.3067(5) Å,
c = 11.6499(3) Å,
β = 103.876(2)◦
1883.49(10) Å3
4
Volume
Z
Calculated density
Absorption coefficient
F(000)
1.229 Mg m−3
1.625 mm−1
752
Crystal size
Temperature
0.23 × 0.22 × 0.21 mm
293 K
Radiation [CuKα]
Theta range for data collection
Limiting indices
1.54178 Å
4.6◦ – 64.4◦
−4 ≤ h ≤ 10,
−20 ≤ k ≤ 21,
−13 ≤ l ≤ 13
4176/3069 [R(int) = 0.039]
2543
Reflections collected/unique
Observed data [I > 2.0 σ(I)]
Data/restraints/parameter
Goodness-of-fit on F2
3069/0/217
1.03
Final R indices [I > 2 σ(I)]
Largest diff. peak and hole
R1 = 0.0495, wR2 = 0.1525
0.28 and −0.42 eÅ−3

226
N. Latha Rani et al
Figure 2. ORTEP diagram of the molecule with thermal ellipsoids drawn at 50% probability.
of all the collected reflections and absorption corrections were carried out using the APEX
2 package [4]. Crystal structure was solved by direct methods using SHELXS-97 and
was refined by full-matrix least squares refinement against F2 using SHELXL-97 [5].
All nonhydrogen atoms were refined anisotropically and hydrogen atoms were placed in
chemically acceptable positions. Two hundred and seventeen parameters were refined with
3069 unique reflections which converged the residual to R = 0.0495. The bond lengths
and bond angles values are within the expected range. The details of the crystal data and
structure refinement are given in Table 1. Figure 2 shows the ORTEP diagram of the
molecule with thermal ellipsoids drawn at 50% probability. The geometrical calculations
were carried out using PLATON [6]. The molecular and packing diagrams were generated
using Mercury [7]. The bond distances, bond angles and torsion angles are listed in Table 2.
Hydrogen-bond geometry is given in Table 3.
The 5-membered thiophene ring, S1–C2–C3–C4–C5 (ring 1) is sp2 hybridized and
is in planar conformation with a torsion angle of 0.24◦. Both the cyclohexane rings,
C10–C11–C12–C13–C14–C15 (ring 2) and C19–C20–C21–C22–C23–C24 (ring-3), are
sp3 hybridized. They are in chair conformation with a puckering amplitude Q = 0.571(3)
Å, θ = 3.3(3)◦, ϕ = 323(5)4◦ and Q = 0.583(3) Å, θ = 180.0(3)◦, ϕ = 237(9)◦, respectively
[8]. They are well described by the torsion angles 56.17◦ and 57.05◦, respectively, which
suggest that they adopt +synclinal conformations.
The torsion angle of 174.50(18)◦ for N9–C16–N18–C19 shows the deviation of ring-3
(cyclohexane ring) from amide group. The bond distances of C O (O8–C7 = 1.234(2)
Å, O17–C16 = 1.216(3) Å) of amide groups agree with the distances found in the crystal
structure of 1,3-dicyclohexyl-1-(4-nitrobenzoyl)urea [9]. The C–C bond length in thiophene
ring (ring-1, C4–C5) is 1.408 Å. This is less than the corresponding value of 1.475 Å
and greater than 1.383 Å reported for (2Z, 3E)–2,3–bis(2-thinylmethylene)-succinic acid
methanol hemisolvate [10]. The structure exhibits intermolecular hydrogen bonds of the
type N(18)–H(18) . . . O(8) and C(24)–H(24A) . . . O(17) whose symmetry codes are 1−x,
1−y, −z and −x, 1−y, −z, respectively. One can see that the molecules are interlinked by
hydrogen bonds in Figs. 3, 4, and 5.

Synthesis, Characterization, and Hirshfeld Surface Analysis
227
Table 2. Selected bond lengths (Å), angles (◦), and torsion angles (◦) of the compound
S(1)-C(2)
S(1)-C(5)
C(5)-C(6)
C(6)-C(7)
C(19)-C(24)
C(20)-C(21)
C(21)-C(22)
C(10)-C(11)
1.696(3)
1.702(2)
1.502(3)
1.515(3)
1.509(3)
C(10)-C(15)
O(17)-C(16)
C(19)-C(20)
O(8)-C(7)
C(4)-C(5)
C(3)-C(4)
1.519(3)
1.216(3)
1.521(3)
1.234(2)
1.408(3)
1.388(4)
1.332(5)
1.524(5)
1.518(4)
1.527(3)
C(2) -C(3)
C(23)-C(24)
1.512(3)
Selected bond angles (◦)
C2-S1-C5
C3-C2-S1
C2-C3-C4
C3-C4-C5
C4-C5-C6
C4-C5-S1
C6-C5-S1
C5-C6-C7
O8-C7-N9
92.58(14)
111.9(2)
114.0(3)
111.8(2)
123.6(2)
109.69(17)
126.66(17)
117.10(19)
C10-C11-C12
C13-C12-C11
C14-C13-C12
C13-C14-C15
C10-C15-C14
O17-C16-N18
O17-C16-N9
N18-C16-N9
C16-N18-C19
110.19(19)
111.8(2)
111.7(2)
111.5(2)
109.23(19)
126.2(2)
120.67(19)
113.13(19)
122.82(18)
121.20(18)
Selected torsion angles (◦)
C(3)-C(4)-C(5)-C(6) 178.0(2)
S(1)-C(5)-C(6)-C(7) −7.8(3)
C(4)-C(5)-C(6)-C(7) 175.0(2)
C(5)-C(6)-C(7)-O(8) 21.8(3)
C(5)-C(6)-C(7)-N(9) 159.23(19)
O(8)-C(7)-N(9)-C(10) −9.1(3)
O(8)-C(7)-N(9)-C(16) −179.06(18)
C(6)-C(7)-N(9)-C(10) 171.94(18)
C(6)-C(7)-N(9)-C(16) 1.9(3)
C(11)-C(10)-N(9)-C(7) −82.5(2)
C(11)-C(10)-N(9)-C(16) 88.0(2)
C(15)-C(10)-N(9)-C(7) 151.60(19)
C(15)-C(10)-N(9)-C(16) −37.9(2)
N(9)-C(10)-C(11)-C(12) 177.2(2)
C(15)-C(10)-C(11)-C(12) −57.0(3)
N(9)-C(10)-C(15)-C(14) −175.67(18)
C(11)-C(10)-C(15)-C(14) 58.3(3)
C(10)-C(11)-C(12)-C(13) 54.1(3)
C(19)-C(20)-C(21)-C(22) −58.1(3)
C(22)-C(23)-C(24)-C(19) 56.2(3)
Hirshfeld Surface Analysis
Hirshfeld surfaces and the associated 2D-fingerprint plots were calculated using Crystal-
Explorer [11]. Hirshfeld surface analysis of a crystal structure is an approach wherein
internuclear distances and angles, crystal packing diagrams are studied extensively [12].

228
N. Latha Rani et al
Table 3. Hydrogen bond geometry [Å, ◦]
D–H . . . A
D–H
H . . . A
D . . . A
D–H . . . A
N(18)–H(18)..O(8)(a)
C(10)–H(10)..O(8)∗
C(19)–H(19)..O(17)∗
C(24)–H(24A)..O(17)(b)
0.86
0.98
0.98
0.97
2.15
2.40
2.44
2.51
2.993(2)
2.740(3)
2.849(3)
3.460(3)
168
100
105
165
∗Intramolecular hydrogen bond interactions.
Note: Symmetry codes: (a) 1−x,1−y,−z; (b) −x,1−y,−z.
Figure 3. Packing of molecules when viewed down a-axis.
Figure 4. Packing of molecules when viewed down b-axis.

Synthesis, Characterization, and Hirshfeld Surface Analysis
229
Figure 5. Packing of molecules when viewed down c-axis.
Table 4 shows the contributions of various intermolecular contacts to the Hirshfeld surface.
The highest contributor is H . . . H, which is 69.1% and least is 0.3% for H . . . N.
Figure 6 shows surface that has been mapped over a dnorm. The dominant interactions
between amine N–H and carbonyl O atoms can be seen in the Hirshfeld surfaces as the
bright red areas.
Figure 7 shows the fingerprint plots. Figure 7a shows H . . . H (69.1%) contribution
of intercontact to the Hirshfeld surfaces. Features along the diagonal occur due to H . . . H
contacts. Figures 7b, 6c, and d show the intercontacts H . . . O (13.8%), H . . . C (8.3%),
Table 4. Hirshfeld surface: Percentage of various intermolecular contacts con-
tributed to the Hirshfeld surface
Inter-contacts
Contribution (%)
H H
H O
H C
H S
69.1
13.8
8.3
8.2

230
N. Latha Rani et al
Figure 6. Hirshfeld surfaces mapped with dnorm for the visualization of the compound.
Figure 7. Fingerprint plots of the compound, (a) H . . . H, (b) H . . . O, (c) H . . . C, (d) H . . . S,
showing the percentage contribution of the contacts to the total Hirshfeld surface area for the molecule.

Synthesis, Characterization, and Hirshfeld Surface Analysis
231
and H . . . S (8.2%), respectively. The blue points on the plot indicate the contributions to
the surface [13].
Acknowledgment
Authors are thankful to IOE, Vijnana Bhavan, University of Mysore, Mysore for providing
the single-crystal X-ray diffraction facility.
Funding
N. Latha Rani is thankful to the UGC, New Delhi, for RFSMS fellowship.
References
[1] Agata, S., Monika, W., Maria, D., Ewa, J. W., Agnieszka, K., et al. (2008). Phosphorus Sulfur
Silicon Relat. Elem., 183(11), 2669–2677.
[2] Carmellina, D. B., & Cristina, L., (2009). Farmacia, 57, 473–478.
[3] Carmellina, D. B., Badiceanu, A. M., Constantin, D., & Cristina, L., (2009). Farmacia, 57,
771–779.
[4] Bruker, APEX2, SAINT and SADABS, (2009). Bruker AXS Inc., Madison, Wisconsin, USA.
[5] Sheldrick, G. M. (2008). Acta Cryst., A64, 112.
[6] Spek, A. L. (1990). Acta Cryst., A46, 34.
[7] Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., et al. (2008). J. Appl.
Cryst., 41, 466.
[8] Cremer, D., & Pople, J. A. (1975). J. Amer. Chem. Soc., 97, 354–358.
[9] Dhinaa, A. N., Jagan, R., Sivakumar, K., & Chinnakali, K. (2010). Acta Cryst., E66, 01291.
[10] Venugopala, K. N., Girija, C. R., Chopra D., Shahina Begum, N., & Rao, G. K. (2007). Acta
Cryst., E63, o3722.
[11] Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D., et al. (2012).
CrystalExplorer, Version 3.0. University of Western Australia.
[12] Spackman, M. A., & Jayatilaka, D. (2009). Cryst. Eng. Comm., 11, 19–32.
[13] Spackman, M. A., & McKinnon, J. J. (2002). Cryst. Eng. Comm., 4, 378–392.
[14] McKinnon, J. J., Jayatilaka, D., & Spackman, M. A. (2007). Chem. Commun., 3814–3816.