Optimization of interactions in crystal packing revealed
by crystal structures [ethyl 2-(formylamino)-3-thien-2-yl-2(thien-2-ylmethyl)propanoate and ethyl 3-(5-bromothien-2-yl)2-[(5-bromothien-2-yl)methyl]-2-(formylamino)propanoate]
Lakshminarasimhan Damodharana, Vasantha Pattabhia,*,
Manoranjan Beherab, Sambasivarao Kothab
a
Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai 600 025, India
b
Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400 076, India
Abstract
The title compounds, C15H14NO3S2 (I) and C15H15Br2NO3S2 (II), are derivatives of Aib (a-aminoisobutyric acid) with thiophene rings
substituted at the Ca position. The Ca substitution causes the backbone to assume an extended conformation in the crystal structure. N – H and
C– H donors share the thiophene ring p system for X– H· · ·p interactions. The packings of the molecules are stabilized by intermolecular
N– H· · ·O, C– H· · ·O, C –H· · ·p and C– H· · ·Br hydrogen bonds. Br· · ·O interactions and a weak dihydrogen bond have also been observed in
the crystal structure of II. The packing adopted by II has maximized the number of interactions that are possible.
Keywords: Modified amino acid; Aib derivatives; Dihydrogen bond; p· · · p interaction; Bifurcated p-interaction; Isofunctional hydrogen bonds
1. Introduction
2.1. Synthesis
An analysis of the structural variations due to
substitution at Cb atoms of Aib and incorporating these
amino acids in a peptide sequence is an interesting
proposition (Karle et al. [1], Ramesh and Balaram [2],
Formaggio et al. [3] and Toniolo et al. [4]). In this context a
structural study on Ca,a-dithiophenyl glycine, which is a
new structural variant of Aib, was undertaken.
The synthetic strategy for the preparation of compound I
starts with 2-bromomethyl thiophene a, synthesized inturn
from 2-hydroxymethylthiophene by treatment with
phosphorous tribromide in benzene. Compound a, upon
reaction with ethylisocyanoacetate in the presence of a
phase-transfer catalyst such as tetrabutylammonium hydrogensulfate(TBAHS) in acetonitrile/potassium carbonate,
gave an intermediate coupling product, which was hydrolyzed in diethyl ether in the presence of concentrated
hydrochloric acid at 0 8C to afford I. Along similar lines,
compound II was prepared from 5-bromo-2-bromomethyl
thiophene b (Schemes 1 and 2).
2. Experimental
The compounds C15H14NO3S2 (I) and C15H15Br2NO3S2
(II) are derivatives of Aib and were crystallized from
n-propanol and iso-propanol, respectively, by slow
evaporation.
2.2. Data collection, structure solution and refinement
Data on both compounds were collected with a SMART
CCD diffractometer (Bruker [5]); cell refinement and data
reduction have been performed using SAINT (Bruker [6]).
Structure solution and refinement were carried out using
102
Scheme 1. Synthesis of compound I.
Scheme 2. Synthesis of compound II.
Table 1
Crystal and diffraction parameters for compounds I and II
Identification code
I
II
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C15H14NO3S2
320.39
293(2) K
0.71073 Å (Mo Ka)
Orthorhombic
Pbca
C15H15Br2NO3S2
481.22
293(2) K
0.71073 Å (Mo Ka)
Monoclinic
P21 =c
Unit cell dimensions (Å)
(Å)
(Å)
(8)
a ¼ 10:823ð5Þ
b ¼ 15:484ð8Þ
c ¼ 19:011ð9Þ
a ¼ 10:081ð3Þ
b ¼ 20:819ð7Þ
c ¼ 8:846ð3Þ
b ¼ 94.23(1)
Volume (Å3)
Z
Density (calculated) (Mg/m3)
Absorption coefficient (mm21)
Fð000Þ
Crystal size (mm)
u range for data collection
3186(3)
8
1.336
0.342
1336
0.4 £ 0.25 £ 0.1
2.14–27.378
1851.4(11)
4
1.726
4.616
952
0.50 £ 0.37 £ 0.24
1.96–26.038
Index ranges
213 ˆ h ˆ 13; 218 ˆ k ˆ 18;
223 ˆ l ˆ 23
212 ˆ h ˆ 12; 225 ˆ k ˆ 25;
210 ˆ l ˆ 10
Reflections collected
Independent reflections
Completeness to u ¼ 27:378
Absorption correction
23628
3399 ½RðintÞ ¼ 0:159
91.30%
None
Refinement method
Data/restraints/parameters
Goodness-of-fit on F 2
Final R indices ½I . 2sðIÞ
R indices (all data)
Largest diff. peak and hole (e Å23)
Full-matrix least-squares on Fo2
3399/19*/189
1.041
R1 ¼ 0:081; wR2 ¼ 0:210
R1 ¼ 0:118; wR2 ¼ 0:235
0.475 and 20.392
19056
3639 ½RðintÞ ¼ 0:036
97.10%
Semi-empirical from equivalents
ðTmax ¼ 0:4038; Tmin ¼ 0:2062Þ
Full-matrix least-squares on Fo2
3639/0/209
1.021
R1 ¼ 0:042; wR2 ¼ 0:096
R1 ¼ 0:056; wR2 ¼ 0:102
1.102 and 20.847
*Bond distances are restrained for disordered atoms.
103
the SHELXS 97 and the SHELXL 97 program, respectively
(Sheldrick, [7]); Crystal data are given in Table 1.
The hydrogen atoms were fixed geometrically at calculated
positions (N – H ¼ 0.86 Å and C – H ¼ 0.93 Å). The
difference Fourier map shows alternate positions for S10
and C13 atoms of the thiophene ring of I suggesting
rotational disorder of the B ring through the bond C8 –C9.
Site occupancy factor for the disordered atoms were refined.
Average standard deviations in bond lengths and bond
angles are 0.006 Å and 0.38, respectively, in both
compounds. The coordinates have been submitted to the
Cambridge structural data base and accession numbers are
CCDC 234601 and CCDC 234602 for I and II, respectively.
Compounds I and II crystallized with a single molecule
in the asymmetric unit. The Br substituted compound (II)
crystallized in a lower symmetry space group ðP21 =cÞ;
whereas compound I crystallized in a higher symmetry
space group ðPbcaÞ: The ORTEP diagrams of I and II are
shown in Fig. 1.
3. Results and discussion
Fig. 1. Crystal structures of (a) compound I and (b) compound II with 50%
probability displacement ellipsoids and atomic numbering schemes.
The backbone torsion angles ðf; cÞ of both compounds
adopt an extended conformation [C14 – C1 – N1 – C17
ðfÞ ¼ 179.6(3)8 and 2 175.4(3)8; N1 – C1 – C14 – O15
ðcÞ ¼ 2 179.8(3)8 and 177.0(3)8 for I and II, respectively].
The N-formyl substitution in both compounds have folded
[C1 – N1 –C17 – O17 ¼ 1.1(6)8 and 0.7(6)8 for I and II,
respectively] and ethyl ester substitution in both compounds
have extended [C1 – C14 – O15 – C15 ¼ 2 179.7(3)8 and
178.9(3)8 for I and II, respectively] conformation. The S
atom (S4 and S10) in each thiophene ring pointing towards
the ethyl ester chain are involved in a weak S· · ·C
intramolecular interaction with C14 in both compounds.
The angles between the thiophene ring planes are 58.2(2)8
Fig. 2. C –H· · ·p and N–H· · ·p interactions with thiophene ring and C–H· · ·O interactions observed in the crystal packing made of compound I.
104
Table 3
Hydrogen bond geometry and other interactions for II (Å and 8)
D–H· · ·A
Intramolecular
N1– H1· · ·O14
C2–H2B· · ·O17
C8–H8A· · ·O17
C14· · ·S4
C14· · ·S10
Intermolecular
N1– H1· · ·O17i
C16–H16A· · ·O14ii
p· · ·p interactions
Cg1· · ·Cg1iii
Cg2· · ·Cg2i
Cg2· · ·Cg2iv
Br interactions
O17· · ·Br5–C5v
O17· · ·Br11–C11vi
C5–Br5· · ·C17vii
Br· · ·p interactions
Br5· · ·Cg1viii
Br11· · ·Cg2iii
Fig. 3. Stereoview of the molecules showing, H· · ·H, three-center N–H· · ·O
and C– H· · ·O hydrogen bond interactions, and Br· · ·p interactions for
compound II.
(average value for the disordered ring) and 64.9(2)8 for I and
II, respectively.
The N –H· · ·O and C – H· · ·O hydrogen bonds, and p
interactions stabilize the packing of the molecules in I
(Fig. 2) and II (Fig. 3). The hydrogen bonding parameters
are given in Tables 2 and 3, respectively. Compound II
has more interactions (14) than I (7) due to the
bromine substitutions. In II the bromine atom makes strong
Br· · ·O and C –H· · ·Br interactions with the O17 and C17
atoms. A strong N1 – H1· · ·O14 intramolecular hydrogen
bond is present in both structures (C5-conformation,
Table 2
Hydrogen bond geometry and other interactions for I [Å and 8]
D –H· · ·A
Intramolecular
N1–H1· · ·O14
C14· · ·S4
C14· · ·S10
Intermolecular
C5 –H5· · ·O17i
p interactions
N1–H1· · ·Cg1ii
C17–H17· · ·Cg1ii
C16–H16· · ·Cg1iii
d(D–H)
d(H· · ·A)
d(D· · ·A)
,(DHA)
0.86
–
–
2.17
–
–
2.616(4)
3.442(4)
3.425(5)
112
–
–
0.93
2.43
3.187(5)
138
0.86
0.93
0.93
3.03
3.22
2.96
3.685(3)
3.806(5)
3.868(5)
134
122
159
Symmetry transformations used to generate equivalent atoms: (i) 2x þ
1=2; y þ 1=2; z; (ii) 1 2 x; 2y; 1 2 z; (iii) 2x; 2y; 1 2 z:: Cg1 2 (S4, C3,
C7, C6, C5).
D(D –H)
d(H· · ·A)
d(D· · ·A)
,(DHA)
0.86
0.97
0.97
–
–
2.26
2.58
2.44
–
–
2.662(4)
3.178(5)
3.013(4)
3.443(4)
3.238(5)
109
120
118
–
–
0.86
0.97
2.35
2.93
3.055(4)
3.612(6)
140
129
–
–
–
–
–
–
4.199(3)
4.425(3)
4.424(3)
–
–
–
–
–
–
–
–
–
3.074(3)
3.132(3)
3.449(3)
170.3(2)
167.8(1)
135.0(1)
–
–
–
–
4.112(2)
3.899(2)
–
–
Symmetry transformations used to generate equivalent atoms: (i) x;
2y þ 1=2; z 2 1=2; (ii) 2x 2 1; 2y þ 1; 2z þ 1; (iii) 2x; 1 2 y; 2 2 z; (iv)
x; 1=2 2 y; 1=2 þ z; (v) 2x; 21=2 þ y; 3=2 2 z; (vi) 1 þ x; 1=2 2 y; 1=2 þ z;
(vii) 2x; 1=2 þ y; 3=2 2 z; (viii) 2x; 2y þ 1; 2z þ 1; Cg1 2 (S4, C3, C7,
C6, C5); Cg2-(S10, C9, C13, C12, C11).
N –Ca – C0 ¼ 105.5(3)8 and 106.5(3)8 in I and II respectively) (Toniolo, et al. [8] and Ashida et al. [9]). In I the
proton of N1 forms a strong intramolecular hydrogen bond
with O14, whereas in II it forms a strong three-center
hydrogen bond with O14 and O17 (Jeffrey et al. [10]). In II
the O17 atom interacts with the symmetry related Br5 and
Br11 atoms dimerising the molecules (Fig. 4).
3.1. Weak dihydrogen bond
Hydrogen atoms H15A and H15B attached to the C15
atom of the ethyl ester chain have close interactions with
centrosymmetrically related H15A and H15B atoms (Fig. 3).
The protons face each other and lie in a plane forming weak
dihydrogen bonds (Desiraju and Steiner [11]). This may be
due to the weak C – H· · ·O interaction between C16 and O14
in the vicinity of the protons (Table 3).
3.2. N – H· · ·p and C – H· · ·p interactions
of thiophene ring system
The packing of I is stabilized by N – H· · ·p and C –H· · ·p
interactions (Malone et al. [12], Hunter et al. [13]) involving
the A and B thiophene rings. The p electron cloud in the
thiophene A ring is involved in both types of interaction
(Fig. 2).
105
(Fig. 5). The Br5 and Br11 atoms in II participate in p
interactions with rings A and B, respectively (Fig. 5 and
Table 3) (Prasanna & Guru Row [15]).
3.4. Isofunctional replacement of C– H· · ·O hydrogen
bond by Br· · ·O interaction
The C5 –H5· · ·O17 hydrogen bond in I is replaced by a
C5 – Br5· · ·O17 interaction in II. The hydrogen bond
distance in I is 3.187(5) Å (Table 2), whereas in II the
Br5· · ·O17 distance is 3.074(3)Å (Table 3). This is an
isofunctional replacement of a C – H· · ·O hydrogen bond by
a Br· · ·O interaction (Steiner et al. [16]) (Figs. 2 and 3).
The N–H· · ·O intermolecular hydrogen bond has been
observed in the packing of II (Table 3), whereas this
interaction is replaced by a strong N–H· · ·p interaction with
the thiophene ring system in I (Table 2). This appears to be the
signature of this class of compounds (Damodharan et al. [17]).
3.5. Data base analysis on N –H· · ·p and C – H· · ·p
interactions of thiophene ring systems
Fig. 4. Dimer formation produced by the Br substitution in compound II as
observed in the packing mode.
3.3. Stacking interactions
Stacking interaction is also an important factor in
stabilizing the packing of II (McGaughey et al. [14]).
The compounds contain two thiophene rings (A and B) on
either side of the Ca atom. Two types of stacking
interactions have been observed in the packing of II. In the
A-ring the sulfur atoms are pointing towards each other and
hence are named as Sulfur Inface Stacking (SIS), while in
the B-ring the sulfur atoms are pointing away from each
other and hence are called as Sulfur Outface Stacking (SOS)
A Cambridge structural database (CSD) (Allen and
Kennard [18,19]) search was performed for N –H· · ·p and
C – H· · ·p interactions by assigning the distance from
the proton to the p-system of thiophene to be # 4.0 Å and
the angle between the donor and the centroid of the
thiophene ring to be in 0 –1808 range. There were 6739 hits
for C – H· · ·p and 90 hits for N – H· · ·p interactions, which
are shown as polar plots (Fig. 6a and b). The plots clearly
indicate the predominant occurrence of C – H· · ·p
interactions with an angular range 60– 1808 and a donor
acceptor distance 3.0 –4.0 Å. The density of the spots is
relatively higher in the 120 –1808 range, whereas the density
of N –H· · ·p interactions is higher in the range 60– 1208.
Fig. 5. Stereoview of the packing of the molecules of II showing Sulfur Inface Stacking (SIS) and Sulfur Outface Stacking (SOS) interactions down the c
axis for II.
106
A search for simultaneous occurrence of both types of
interactions with a single thiophene ring treated as a
p-acceptor yielded no hits, suggesting that this phenomenon
is reported for the first time in this work.
This study indicates that H· · ·H, C –H· · ·p and N –H· · ·p
interactions play an important role in crystal packing.
Acknowledgements
This work was supported by the Council of Scientific and
Industrial Research, India. SK thanks RSIC, Mumbai, for
providing the spectral data.
References
Fig. 6. (a) The C–H· · ·p interaction d(H· · ·p)is #4.0 Å and the C–H· · ·p
angle is 08 –1808 (p system is the thiophene ring). Totally 6739 hits were
obtained in CSD. (b) The N –H· · ·p interaction d (H· · ·p) is #4.0 Å and the
N–H· · ·p angle is 08 to 1808. (p- system is the thiophene ring). Totally, 90
hits were obtained in CSD.
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