Probing the Crystal Structure Landscape by Doping: 4-Bromo, 4-Chloro, and 4-Methylcinnamic Acids

Article abstract of DOI:10.1002/anie.201801649

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4-bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4-methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4-chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl-doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of π???π interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.

Full text of DOI:10.1002/anie.201801649

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Probing the crystal structure landscape by doping: 4-bromo, 4-
chloro and 4-methylcinnamic acids
Authors: Gautam R. Desiraju, Shaunak Chakraborty, and Sumy
Joseph
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801649
Angew. Chem. 10.1002/ange.201801649
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Probing the crystal structure landscape by doping:
4
-bromo, 4-chloro and 4-methylcinnamic acids
Shaunak Chakraborty, Sumy Joseph and Gautam R. Desiraju*
Abstract: Accessing the data points in the crystal structure
landscape of a molecule is a challenging task, either experimentally
or computationally. We have charted the crystal structure landscape
nature rather different from it. This makes it a handy tool in the
[9]
exploration of the crystal structure landscape. This is so
because of the packing diversity that is caused by the very weak
C–H···F hydrogen bonds that might manifest themselves after
of
4-bromocinnamic
acid
(4BCA)
experimentally
and
[10]
the stronger interactions are paired off and insulated.
computationally: experimental doping is achieved with 4-
methylcinnamic acid (4MCA) to obtain new crystal structures;
computational doping is performed with 4-chlorocinnamic acid
Multicomponent solids have also proven effective on occasion
by capturing molecular conformations and packing modes that
[
3c, 9b]
cannot be accessed under laboratory conditions.
(4CCA) as a model system, because of the difficulties associated in
parameterizing the Br-atom. The landscape of 4CCA is explored
experimentally in turn, also by doping it with 4MCA, and is found to
bear a close resemblance to the landscape of 4BCA, justifying the
ready miscibility of these two halogenated cinnamic acids to form
solid solutions without any change in crystal structure. In effect,
A stable crystal structure is primarily guided by the principle of
close-packing, according to which the protrusions of one
molecule fit into the voids of another. In cases where the
intermolecular interactions are weak, the structure is driven
almost entirely by packing considerations, i.e., by isotropic
electrostatic dispersion and exchange repulsion terms. A direct
consequence of this is the fact that it is possible for a non-polar
substituent to be replaced by one sterically similar to it, without
4MCA, 4CCA and 4BCA form a commutable group of crystal
structures, which may be realized experimentally or computationally,
and constitute the landscape. Unlike the results obtained by
Kitaigorodskii, all but two of the multiple solid solutions obtained in
the methyl-doping experiments take structures that are different from
the hitherto observed crystal forms of the parent compounds. Even
granted that the latter might be inherently polymorphic, this unusual
observation provokes the suggestion that solid solution formation
may be used to probe the crystal structure landscape. The influence
of∙∙∙ interactions, weak hydrogen bonds and halogen bonds in
directing the formation of these new structures is also seen.
such a replacement bringing about any changes in the crystal
[11]
structure.
This is in accordance with the observations of
[12]
Kitaigorodskii,
who saw that when two compounds A and B
with very similar molecular structures are cocrystallized, two
outcomes may ensue: (1) when A and B have the same crystal
structure, the result is a solid solution (SS) A B1–x with this same
x
crystal structure. Kitaigorodskii selected tolane‒diphenylmercury
as a case in point; (2) when A and B have different crystal
x
structures, solid solutions A B1–x are still formed and they take
either or both parent structures. He selected the anthracene‒
acridine system as representative of this situation. When there
are no distinctly directional interactions that may significantly
affect the packing, there is no enthalpic gain to be achieved in
forming a stoichiometric compound (cocrystal) of A and B, but
there could be some entropic advantage in forming a solid
[
1]
The crystal structure landscape is a mapping of the various
dynamic events occurring during the final stages of the
[
2]
crystallization process. It encompasses diverse crystallization
possibilities available to a molecule, such as polymorphs,
solution A
of strong and directional A···B interactions in the system,
x y
however, the result is mostly a stoichiometric cocrystal A B .
x
B1–x. When there is significant anisotropy in the form
[
3]
pseudopolymorphs and high Z’ variations. Attempts at charting
the landscape computationally have met with some degree of
success; crystal structure prediction (CSP) samples possible
Now what if A were to be doped with B such that the A···B
interactions are neither completely isotropic, nor highly
anisotropic? The expected result in such a scenario could be still
[
4]
crystallization pathways,
but can fail to predict the final
experimental crystal form because it ignores kinetic factors
x
a SS A B1–x, but in a crystal structure that is neither that of A nor
[5]
associated with the process. Most putative structures in the
landscape are difficult to isolate under laboratory conditions, but
knowledge of the various packing possibilities is certainly useful,
especially when a particular solid form can be associated with a
B; rather this would adopt a different packing, effectively
allowing experimental access to points in the landscape that
were hitherto unavailable. An SS of two compounds crystallizing
in a new structure type, which is not taken by either pure
compound, is almost novel, and we have seen only a few
[
6]
particular property.
[13]
examples.
detail.
This communication explores this possibility in
The initial stages of the crystallization process can be probed
[
7]
with spectroscopy, whereas crystallography can chart out the
The isosteric, but electronically different characters of the F and
the H atoms have been exploited in landscape exploration
exercises. We have shown in a recent report that partial fluoro-
[
3d, 8]
final steps.
Small chemical perturbations at certain
innocuous positions of the molecule can be used to probe
regions of the landscape that are otherwise inaccessible. The F-
atom, although sterically like the H-atom, has an electronic
[9]
substitution, achieved in SS of fluorocinnamic acids, can serve
as a finer probe in the landscape of unsubstituted cinnamic acid
[
13a]
than the coarser full fluoro-substitution.
The question that
naturally arises at this point is whether this principle is
applicable to other atom pairs as well. The bromine (Br) atom
[
a]
S. Chakraborty, Dr. S. Joseph, Prof. G. R. Desiraju
Solid State and Structural Chemistry Unit
Indian Institute of Science
and the methyl (Me) group, with their closeness of volume
3
(
24.4 and 24 Å respectively), have the potential to be
Bangalore 560 012, India
E-mail: gautam.desiraju@gmail.com
exchanged in crystal structures without bringing about any
deep-seated changes, if only geometrical effects are
[
14]
important.
However, their very different electronic nature
Supporting information for this article is given via a link at the end of
the document.
could change this outcome and this is what makes them an
attractive test pair in the present context. Profiling the
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landscape of a brominated molecule presents an additional
challenge because of the anisotropy and polarizability of the Br
atom and the resultant computational difficulties associated with
it. We therefore chose to explore the landscape of 4-
bromocinnamic acid (4BCA) by doping it with 4-methylcinnamic
acid (4MCA).
equal concentrations of 4BCA and 4MCA. It is a linear ribbon
with type I inter-sheet Br···Br contacts, and the non-zero
dihedral angle between adjacent sheets is the point of difference
from (4-7-15) (Figure 2). A γ structure is obtained at high
concentrations of 4MCA [P2
1
/n; a = 6.014(2) Å, b = 4.970(2) Å, c
=
28.312(12) Å, β= 90.74(2) °] which we label (6-5-28). It grows
along the 2
1
axis via type II (
1
2
= 91.24˚,  = 172.18˚) Br···Br
4
BCA [ZZZOJI03; P2
1
/n; a = 6.8823(2) Å, b = 3.90430(10) Å, c =
(
interspersed with Me groups) contacts (Figure 2). This contact
31.4618(12) Å, β= 90.077(3)°] is a structure that may be
[
15]
geometry is conducive to an effective C–H···Br interaction
between the Me group of a 4MCA molecule on one planar sheet,
and the Br atom on a 4BCA molecule on the one adjacent to it.
This orthogonal geometry may also have some additional
stabilization due to a C–H··· interaction between the aromatic
ring and the Me protons (ESI). We have thus obtained three
different types of SS of 4BCA and 4MCA that take none of the
native parent structures. We could also isolate two SS in the (7-
described as a linear ribbon (Figure 1a),
type.
of the (7-4-31)
[
16]
This 4Å structure consists of stacks of planar sheets
containing laterally C–H···O hydrogen bonded 4BCA molecules.
[
15]
Horizontally related stacks are offset with respect to each
other according to the geometric demands of Br···Br quasi type
I/II contacts (ESI). 4BCA molecules in vertically related stacks
can be produced by simple translation operations; it is a β
structure. 4MCA [ZZEFW01; P; a = 7.968(2) Å, b = 9.144(2)
Å, c = 7.733(2) Å, α = 106.87(2) °, β = 125.46(2) °, γ =
[17]
4
1
-31) structure, at 4BCA:4MCA ratios of 57:43 and 79:21 (Table
). These are the only two cases among all our experiments
8
1
6.87(2) °], on the other hand, is a planar sheet structure (Figure
b). We call it a (8-9-8) structure. The 4MCA molecules in
vertically related stacks can be produced by inversion operations, where we isolated SS in the native structures of one of the
i.e., it is an
α
structure. From the trends observed by
parent compounds. We also see from Table 1 that SS 3 and 5,
which have very close 4BCA-4MCA ratios, adopt (4-7-15) and
Kitaigorodskii, the SS of 4BCA and 4MCA would also be
expected to take either of the parent structures. However, one
must not rule out the possibility of Br···Br and C–H···Br
interactions in these SS.
(
7-4-31) cells respectively. This indicates that these two
structures are part of the same crystal structure landscape.
Figure 2. Schematic representations of the packing patterns and the
interactions seen in the three types of SS obtained. Please note that use of the
same colour in a stack means that the sheets are all related by simple
translation. (a) shows the packing in the (4-7-15) structures, and (b) and (c)
show the type I interactions seen in the 4BCA-4MCA and 4CCA-4MCA
systems respectively. (d) shows the packing in the (6-5-28) structures, (e) and
(f) show the type II interactions seen in the 4BCA-4MCA and 4CCA-4MCA
systems respectively. (g) shows the packing pattern of the (15-4-30) structures,
and (h) shows the interactions in this structure in the 4BCA-4MCA system.
The (15-4-30) structure was not found experimentally in the 4CCA-4MCA
system. Like before, use of the same color indicates symmetry equivalence.
Figure 1. (a) Schematic representation of the linear ribbon structure of 4BCA.
Both the blue and green sheets consist of laterally C–H···O hydrogen bonded
4BCA molecules. Throughout this paper, use of the same color in a stack
indicates symmetry equivalence, i.e. the molecules are related by a simple
translation operation. (b) shows a schematic representation of the planar sheet
structure of 4MCA. 4MCA molecules in vertically related sheets are related by
inversion operations as indicated by different shades of green.
We obtained SS over a broad range of concentrations, but in
multiple structure types that are neither the native structure of
Having obtained three different types of SS of 4BCA and 4MCA,
we were curious as to whether these three structures would be
found in the CSP of 4BCA. However, given the technical
difficulties related to the anisotropy and polarizability of the Br
atom, we decided to search for a system that would effectively
model 4BCA, but would also be easier to handle computationally.
The Cl atom, being geometrically and electronically like Br, in
addition to being considerably lighter, seemed to be a likely
candidate. We therefore chose to explore 4-chlorocinnamic acid
4BCA nor that of 4MCA (Fig. 1). This is a highly unusual
observation. The SS obtained when the concentration of 4BCA
is higher than that of 4MCA is a planar sheet, but it is a β
structure [P; a = 3.907(9) Å, b = 7.580(19) Å, c = 15.05(4) Å, α=
101.77(6) °, β= 92.87(13) °, γ= 100.63(9) °] where the nearest
molecules are related by translation operations. It, unlike 4BCA
or 4MCA, is classified as a (4-7-15) structure. The Br···Br
contact geometry in this structure is type I, as opposed to quasi
type I/II in (7-4-31) (ESI). Another β structure [C2/c; a =
(
4CCA), which in its pure form is isostructural with pure 4BCA,
as a model. Naturally, this led to an experimental exploration of
the landscape of 4CCA itself by methyl doping. Interestingly, the
SS of 4CCA and 4MCA follow the same composition-structure
correlation as the 4BCA-4MCA system (ESI). We see the (4-7-
14.868(8) Å, b = 3.9586(15) Å, c = 30.040(12) Å, β =
103.964(16) °], classified as (15-4-30), is obtained at roughly
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1
5) structure at relatively high concentrations of 4CCA, while
On examining the crystal structures 4ICA and 9% 4ICA doped
4MCA, the latter crystallizing with a (6-5-28) structure (ESI), it
occurred to us that the CSP protocol, which takes only close-
packing into consideration, had likely overlooked the interaction
component, and this was why the (6-5-28) structure with the
type II halogen bond geometry could not be found in the CSP
results. A CSD search for structures with these cell parameters
relatively low concentrations of it produce the (6-5-28) structure.
We could not isolate any SS in the (15-4-30) structure for the
4CCA-4MCA system, but interestingly, in 4CCA too we see the
unique phenomenon of the solid solutions taking crystal
structures different from either of the native parent structure
types.
1
returned a polymorph of 4-formylcinnamic acid [COWRIP; P2 /n;
a = 6.261(2) Å, b = 4.825(1) Å, c = 27.614(9) Å, β=91.54(2) ˚] as
a hit (ESI). This is essentially isostructural with these SS and is
held together by orthogonal interactions between the carbonyl
groups of adjacent molecules (Figure 4).
To find out if the (6-5-28) structure would be seen when the
molecule has a high propensity for the formation of orthogonal
type-II interactions, we carried out cocrystallization experiments
with 4-iodocinnamic acid (4ICA) and 4MCA. We isolated a
structure containing 91% 4MCA and 9% 4ICA [P2
.0085(5) Å, b = 4.908(3) Å, c = 28.126(18) Å, β = 90.82(4) °],
which is a (6-5-28) structure, and is different from the structure
of 4ICA itself [WAMZOZ, P2 /n; a = 4.118(2) Å, b = 6.274(4) Å, c
34.672(2) Å, β= 90.32(2) °]. Both 4ICA and the 9% 4ICA-
1
/n; a =
6
1
=
doped 4MCA exhibit type II I···I interactions, and it is obvious
that these interactions and possibly C–H···I hydrogen bonds in
case of SS 26, drive the molecules to pack thus (ESI).
Table 1. Solid solutions of 4BCA and 4CCA with 4MCA
SS of 4BCA and 4MCA
SS of 4CCA and 4MCA
SS
1
4BCA:4MCA
60:40
56:44
76:24
57:43
79:21
6:94
Structure
SS
11
12
13
14
15
16
17
18
19
4CCA:4MCA
74:26
Structure
(4-7-15)
(4-7-15)
(4-7-15)
(7-4-31)
(7-4-31)
(6-5-28)
(6-5-28)
(15-4-30)
(15-4-30)
(15-4-30)
(4-7-15)
(4-7-15)
(4-7-15)
(4-7-15)
(4-7-15)
(4-7-15)
(6-5-28)
(6-5-28)
(6-5-28)
2
62:38
Figure 4. (a) shows where the (6-5-28) structure occurs in the CSP of
COWRIP with DREIDING. (b) Packing diagram and (c) orthogonal interactions
in COWRIP.
3
54:46
4
49:51
5
65:35
We hypothesized that since the positive charge on the C atom of
the formyl group on the 4-position is accounted for, there is a
good chance that a structure close to (6-5-28) may turn up in
CSP of COWRIP; such a structure indeed arises at rank 2 with
DREIDING. Thus, with the possible interactions accounted for,
all the experimental structures may be obtained by the CSP
protocol. The (4-7-15), (7-4-31), (15-4-30) and (6-5-28)
structures are all parts of the landscape of 4CCA, and by token
of the identical behaviour of 4BCA under the same
cocrystallization protocols, of the landscape of 4BCA as well.
Indeed there is just the one landscape and all the 4MCA, 4CCA
and 4BCA structures identified experimentally and/or
computationally constitute a commutable set of crystal structures
within this landscape.
6
66:34
7
6:94
20:80
8
43:57
46:54
51:49
9:91
9
11:89
10
To ascertain if these structures are indeed part of the landscape
of 4CCA, we performed a computational CSP experiment with
the 4CCA molecule as an input (ESI). The (4-7-15), (15-4-30)
and (7-4-31) structures turned up in the energy-density plot
[18]
(
Figure 3). We even obtained a structure like that of 4MCA, but
the (6-5-28) structure was not found (ESI).
The mutual dissolution behaviour of 4BCA and 4CCA, and their
ternary SS behavior with 4MCA place this on an even firmer
footing. 4BCA and 4CCA exhibit continuous solubility with each
other (SS 20-25) without any structural changes over the whole
range of composition, meaning their energy hypersurfaces are
similar not only in their general features, but also in the positions
of their minima. The 4BCA-4CMA and 4CCA-4MCA systems
also have similar phase diagrams as shown in Figure 5. Further
details are given in the ESI.
Figure 3. Energy-density plot of the structures obtained from the CSP of
4
CCA. Structures close to the experimental structures occur in the highlighted
The ternary SS (27 and 28) of 4CCA, 4BCA and 4MCA are both
different. They are distinct from either 4BCA (which is the same
as 4CCA) or 4MCA. This makes a total of four structure types in
region.
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COMMUNICATION
this set of compounds. Yet, all four structures are found in the
same landscape, showing clearly that the latter is a pool from
which equivalent structures may effectively be drawn.
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3]
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a) D. Braga, F. Grepioni, Chem. Commun. 2005, 3635-3645; b) A.
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Grobelny, T. S. Thakur, G. R. Desiraju, Cryst. Growth Des. 2011, 11,
We have explored the structural landscapes of 4BCA and 4CCA
using bromo-methyl and chloro-methyl exchange phenomena as
tools. One may draw several conclusions: (1) 4CCA, because of
the geometric and electronic similarities of the Cl and the Br
atoms, is a good model for charting the landscape of the more
computationally challenging 4BCA. (2) 4BCA and 4CCA have
virtually identical structural landscapes and so they are
completely miscible. (3) Isolation of solid solutions with crystal
structures that are different from either of the parent structures
hints that interaction directionality plays a role in the packing of
molecules. To the best of our knowledge, this is the first such
report in the context of chloro-methyl and bromo-methyl
exchange experiments.
2637-2653; d) T. S. Thakur, R. Sathishkumar, A. G. Dikundwar, T. N.
Guru Row, G. R. Desiraju, Cryst. Growth Des. 2010, 10, 4246-4249; e)
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4]
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Chem. Int. Ed. 2005, 44, 3769-3773; c) A. R. Oganov, A. O. Lyakhov,
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Shtukenberg, D. J. Carter, T.-Q. Yu, J. Yang, M. Chen, P. Raiteri, A. R.
Oganov, B. Pokroy, I. Polishchuk, P. J. Bygrave, G. M. Day, A. L. Rohl,
M. E. Tuckerman, B. Kahr, J. Am. Chem. Soc. 2016, 138, 4881-4889.
G. R. Desiraju, Nat. Mater. 2002, 1, 77-79.
[
[
5]
6]
a) L. Yu, Acc. Chem. Res. 2010, 43, 1257-1266; b) C. M. Reddy, S.
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J. Schmidt, in Pure Appl. Chem., Vol. 27, 1971, p. 647; d) G. Bolla, A.
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[
[
7]
8]
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2005, 1531-1533.
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Smith, CrystEngComm 2009, 11, 359-366; b) E. V. Boldyreva, Acta
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Figure 5. Melting point vs. composition plots of (a) the 4BCA-4CCA, (b) the
4BCA-4MCA, and (c) the 4CCA-4MCA systems.
[
9]
a) R. Dubey, M. S. Pavan, G. R. Desiraju, Chem. Commun. 2012, 48,
9
1
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It is likely that we would obtain non-stoichiometric mixed crystals
in a different structure type when the interactions involved are
neither isotropic enough to allow the formation of a solid solution
in one of the native parent structure types, nor strong/directional
enough to give rise to a stoichiometric compound. We have also
noted in a prior study that at least two of these structure types,
namely (4-7-15) and (7-4-31), are part of the crystal structure
landscape of unsubstituted CA. Another structure type (4-7-31)
which is seen in the CSP of 4CCA, is also a part of the
landscape of unsubstituted CA. One may also draw in the
unsubstituted compound into the landscape. These structures
constitute a closed set, recurring irrespective of the substituent
[10] V. R. Thalladi, H.-C. Weiss, D. Bläser, R. Boese, A. Nangia, G. R.
Desiraju, J. Am. Chem. Soc. 1998, 120, 8702-8710.
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(
H, F, Cl, Br or Me) used in the exercise; this proves the
generality of the concept of the crystal structure landscape.
3607-3615; c) M. A. Khoj, C. E. Hughes, K. D. M. Harris, B. M. Kariuki,
Cryst. Growth Des. 2017, 17, 1276-1284; d) J. d. C. Fonseca, J. C.
Tenorio Clavijo, N. Alvarez, J. Ellena, A. P. Ayala, Cryst. Growth Des.
2
018, 18, 3441-3448.
14] a) M. Dabros, P. R. Emery, V. R. Thalladi, Angew. Chem. Int. Ed. 2007,
6, 4132-4135; b) M. Paul, S. Chakraborty, G. R. Desiraju, J. Am.
Experimental Section
[
4
Experimental details are provided in the supplementary material.
Chem. Soc. 2018, 140, 2309-2315.
[
[
15] J. A. R. P. Sarma, G. R. Desiraju, Acc. Chem. Res. 1986, 19, 222-228.
16] The numbers are the closest integer approximations to the cell
dimensions, as per the convention described in reference 9a.
17] α, β and γ are structure types described in M. D. Cohen, G. M. J.
Schmidt, J. Chem. Soc. 1964, 1996-2000.
Acknowledgements
[
[
SC thanks the IISc for a SRF and GRD thanks the DST, New
Delhi, for the award of a JC Bose Fellowship.
18] The CSP exercises were carried out using only the pure components
as input. If solid solutions are to be used as input, the presence of two
different atoms at the same crystallographic site must be accounted for,
because such
a procedure is liable to cause problems with the
Keywords: Solid solution • Crystal structure landscape • Crystal
engineering • Crystal structure prediction • Doping
geometry optimization and the force fields.
[
1]
a) G. R. Desiraju, Acta Cryst. B 2017, 73, 775-778; b) S. Tothadi, G. R.
Desiraju, Philos. Trans. Royal Soc. A 2012, 370, 2900.
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Experimental and computational
crystal structures of 4-chloro, 4-bromo
and 4-methylcinnamic acids, and their
binary and ternary solid solutions
define a single landscape.
Shaunak Chakraborty, Sumy Joseph
and Gautam R. Desiraju*
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Probing the crystal structure
landscape by doping: 4-bromo, 4-
chloro and 4-methylcinnamic acids
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