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Acta Crystallographica Section B

Structural Science,Crystal Engineeringand Materials

ISSN 2052-5206

A top–down approach to crystal engineering of a racemicΔ2-isoxazoline

Giuseppe M. Lombardo, Antonio Rescifina, Ugo Chiacchio, Alessia Bacchiand Francesco Punzo

Acta Cryst. (2014). B70, 172–180

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Acta Cryst. (2014). B70, 172–180 Giuseppe M. Lombardo et al. · Racemic Δ2-isoxazoline

crystal engineering

172 doi:10.1107/S2052520613030862 Acta Cryst. (2014). B70, 172–180

Acta Crystallographica Section B

Structural Science,Crystal Engineeringand Materials

ISSN 2052-5206

A top–down approach to crystal engineering of aracemic D2-isoxazoline

Giuseppe M. Lombardo,a

Antonio Rescifina,a Ugo

Chiacchio,a Alessia Bacchib* and

Francesco Punzoa*

aDipartimento di Scienze del Farmaco, Univer-

sita degli Studi di Catania, Viale Andrea Doria,

6, 95125 Catania, Italy, and bDipartimento di

Chimica, Universita degli Studi di Parma, Parco

Area delle Scienze 17/A, 43124 Parma, Italy

Correspondence e-mail:

alessia.bacchi@unipr.it, fpunzo@unict.it

# 2014 International Union of Crystallography

The crystal structure of racemic dimethyl (4RS,5RS)-

3-(4-nitrophenyl)-4,5-dihydroisoxazole-4,5-dicarboxylate,

C13H12N2O7, has been determined by single-crystal X-ray

diffraction. By analysing the degree of growth of the

morphologically important crystal faces, a ranking of the most

relevant non-covalent interactions determining the crystal

structure can be inferred. The morphological information is

considered with an approach opposite to the conventional

one: instead of searching inside the structure for the potential

key interactions and using them to calculate the crystal habit,

the observed crystal morphology is used to define the

preferential lines of growth of the crystal, and then this

information is interpreted by means of density functional

theory (DFT) calculations. Comparison with the X-ray

structure confirms the validity of the strategy, thus suggesting

this top–down approach to be a useful tool for crystal

engineering.

Received 13 September 2013

Accepted 10 November 2013

1. Introduction

The common approach to crystal engineering is based on

structural analysis of crystal packing aimed at highlighting the

most relevant non-covalent interactions that could make it

possible to control and design the synthesis of the solid state

for compounds of interest. The information gained from the

solid-state arrangement of the building blocks of the crystal

allows a wide range of speculations on possible chemical and

physical ways to enhance or deplete some of these key inter-

actions. In this framework, insight into packing arrangements

provided by the increasingly powerful and easy-to-control X-

ray diffraction instruments makes this task easier to carry out.

However, it is often limited to inspection of the packing

geometry to identify the shortest intermolecular contacts from

which the main interactions responsible for the crystal cohe-

sion are inferred. Moreover, these are usually ascribed a priori

to well established categories such as various kinds of

hydrogen bonds, �–� interactions, and so on. The pitfalls of

this kind of approach have recently been discussed and might

present the risk of subjectivity when ranking structural motifs

only on the basis of geometrical evidence, without also

calculating the interaction energy (Gavezzotti, 2013).

In this paper we invert this conventional approach to crystal

engineering by looking at the crystal morphology, by recalling

that the outer shape of a crystal must contain valuable infor-

mation on the microscopic behaviour at the molecular level

(Weissbuch et al., 1991, 1995, 2003). According to previous

examples (Bacchi et al., 2011), we adopt a rational protocol

that starts by identifying the morphologically important (MI)

faces that are necessarily related to the main factors that build

up the crystal, then performing a geometrical analysis to find

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objectively the directions of the main interactions. We then

derive a quantitative ranking of the energies involved in the

process of the crystal building by means of DFT calculations.

We do not perform a crystal morphology prediction (Bacchi et

al., 2011; Lazo Fraga et al., 2013; Li Destri et al., 2011, 2013;

Punzo, 2011, 2013), but consider the real crystal morphology

that is experimentally measured and indexed on the diffract-

ometer. Possible inconsistencies between predicted and

experimental crystal morphologies could be interpreted on the

basis of molecular structures and bond anisotropies, as well as

on the fact that computational methods do not fully take into

account some relevant experimental factors such as

temperature, supersaturation and growth mechanism, or the

key role played by the solvent in solution crystallization.

We interpret the experimental morphology on the basis of

the periodic bond chain (PBC) theory (Hartman & Bennema,

1980; Bennema et al., 2004), thus assuming that the surface

area corresponding to the most prominent MI faces belongs to

those showing a slower growth rate, which is in turn propor-

tional to the attachment energy (Ea). Although the attach-

ment energy was originally defined as ‘the bond energy

released when a building unit is attached to the surface of the

crystal face concerned’ (Hartman & Perdok, 1955), accord-

ingly to current literature (Punzo, 2011) we define it as the

energy released by attaching a molecule, or a growth slice, to a

growing crystal surface. More specifically, for our purposes, we

consider the energy released as a consequence of the inter-

actions normal to the surface of the formula unit within an

underlying slice (Punzo, 2011). For this reason, instead of

limiting the structural analysis to the crystal packing we

consider the structural and energy landscape provided by each

MI face as resulting from cutting a slab parallel to that face,

thus corresponding to a picture of that particular crystal-

lographic environment. By attaching successive formula units

to the slab, we interpret in fine detail the overall process of

crystal growth, explained on the basis of the final crystal

morphology.

For this work we consider well shaped crystals of dimethyl

(4RS,5RS)-3-(4-nitrophenyl)-4,5-dihydroisoxazole-4,5-dicarb-

oxylate (1) (Quilico & Grunanger, 1955), which belongs to the

�2-isoxazoline class of compounds that are reported to show

antifungal activity (Konopıkova et al., 1992) as well as to act as

herbicides (Munro & Bit, 1986), and which have also been

studied in relation to cycloaddition reactions (Chiacchio et al.,

1996, 2002, 2003, 2004; Quadrelli et al., 2004).

2. Experimental

2.1. X-ray diffraction

The crystal structure of (1), synthesized as reported in the

literature (Quilico & Grunanger, 1955), was determined by

single-crystal X-ray diffraction on a crystal selected from a

batch crystallized from benzene by slow evaporation. Data

were collected with Cu K� radiation (� = 1.5418 A) at room

temperature (293 K) on a Bruker APEX-II CCD diffract-

ometer; H atoms were located from the difference Fourier

map and their coordinates were refined. Crystal data and

structure refinement details are reported in Table 1.

2.1.1. Face indexing. From inspection of the crystallization

batch, it was evident that all crystals presented a similar

growth morphology. This was quantitatively analysed for the

selected crystal by measuring crystal dimensions and indexing

the faces by means of the SCALE procedure embedded in the

APEX2 software (Bruker, 2008). The morphology was

analysed using stereographic projections created by the

programs KrystalShaper (JCrystalSoft, 2013) and WinWullf

(JCrystalSoft, 2009).

2.2. Quantum chemical calculations

All calculations were performed in the gas phase using the

GAUSSIAN09 package (Frisch et al., 2009) using the 6-

311G(d,p) basis set with the DFT functional wB97XD, which

includes empirical dispersion and long-range corrections

(Chai & Head-Gordon, 2008). Single-point energy calcula-

tions were performed on monomers, dimers, trimers and

tetramers, as taken from the X-ray crystal structure, in order

to assess their relative stability. Moreover, in order to gain

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Acta Cryst. (2014). B70, 172–180 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline 173

Table 1Experimental details.

Crystal dataChemical formula C13H12N2O7

Mr 308.25Crystal system, space group Monoclinic, P21/cTemperature (K) 293a, b, c (A) 7.2032 (2), 6.9183 (3), 27.515 (2)� (�) 92.134 (4)V (A3) 1370.23 (12)Z 4Radiation type Cu K�� (mm�1) 1.07Crystal size (mm) 0.90 � 0.45 � 0.25

Data collectionDiffractometer Bruker APEX-II CCDAbsorption correction Multi-scan SADABS (Bruker,

2008)Tmin, Tmax 0.98, 0.99No. of measured, independent and

observed [I > 2�(I)] reflections4957, 2596, 2490

Rint 0.016(sin �/�)max (A�1) 0.609

RefinementR[F 2> 2�(F 2)], wR(F 2), S 0.040, 0.114, 1.05No. of reflections 2596No. of parameters 248No. of restraints 3H-atom treatment All H-atom parameters refined�max, �min (e A�3) 0.30, �0.24

Computer programs: APEX2 (Bruker, 2008), SAINT (Bruker, 2008), SIR97 (Altomare etal., 1999), SHELXTL (Bruker, 2008), SHELXL2013 (Sheldrick, 2008) and WinGX(Farrugia, 1999).

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information on the interaction of a single molecule with the

(001), (010) and ð�1102Þ surfaces, models were built by consid-

ering a single molecule within the crystal with the 6 (or 7)

nearest molecules from the adjacent slab with the proper

Miller indices. For these latter models, the calculations were

performed on the 6 (or 7) slab molecules and on the nearest

interacting single molecule belonging to the adjacent slab.

2.3. Crystal morphology prediction

Prediction and study of the possible crystal morphologies

were performed using a preliminary equilibration protocol, by

means of the Discover module included in Materials Studio 4.4

(Accelrys, 2003), adopting the molecular mechanics approx-

imation and the COMPASS forcefield (Sun, 1998). The

established single-crystal structure was used as the input for

energy minimization. A distance cutoff was selected for

interactions between molecules, applied as 1.5 times the value

calculated in terms of the centroid-to-centroid distance along

each lattice vector. An energy cutoff of �2.49 kJ mol�1 was

also applied and only interactions with a more stabilizing

energy were considered. The morphology protocol itself is

based on the so-called GM method, based on the PBC theory.

For this purpose, the calculations were performed allowing a

minimum interplanar distance (dhkl) of 1.300 A and a

maximum value of 3 for each of the three Miller indices. The

overall number of growing faces was limited to 200. All of

these calculations correspond to 0 K and surface relaxation

was not applied. Furthermore, the surface is considered to be a

perfect termination of the bulk. A detailed description of the

calculation performed can be found in Punzo (2013).

3. Results and discussion

Compound (1) crystallized from benzene as a racemic mixture

in the space group P21/c (Table 1). As shown in Fig. 1, the

molecule consists of a nearly planar core comprising the nitro

group, the phenyl ring and the isoxazoline heterocycle. The

latter bears two methoxyacetyl substituents that stick out

almost perpendicularly in opposite directions from the planar

molecular core [N2—C7—C8—C10 �101.7 (1), N2—O3—

C9—C11 �98.3 (1)�]. The isoxazoline ring is slightly distorted

in an envelope conformation, with the C9 atom deviating by

0.38 A from the ring plane. The molecule bears no obvious

functional groups that suggest strong intermolecular interac-

tions. In such a case, the classical approach adopted in most

papers is to analyse the shortest intermolecular contacts and

to infer that interactions shorter than the sum of van der Waals

radii are possibly stabilizing. This approach has been criti-

cized, because without any energy estimation there is no

reason to exclude the possibility that such short contacts might

be repulsive (Gavezzotti, 2013). We report here this conven-

tional kind of discussion based on interatomic distances, then

contrast it with experimental evidence about preferred growth

directions derived from the macroscopic crystal morphology.

3.1. Analysis of intermolecular contacts

Analysis of the shortest intermolecular contacts indicates a

possible interaction between one O atom of the nitro group

and one electron-poor carboxylic C atom [O2� � �C11i =

3.211 (2) A; symmetry code: (i) �x; 1 � y;�z]. The direc-

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174 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline Acta Cryst. (2014). B70, 172–180

Figure 1Molecular structure of (1), showing displacement ellipsoids at 50%probability for non-H atoms.

Figure 2(a) Molecular charge density map resulting from the DFT calculations.(b) Geometrical analysis of the crystal packing, showing theNO2� � �COOCH3 short contact (black dashed lines), building a centro-symmetric supramolecular dimer, and showing all other short CH� � �Ocontacts as blue dashed lines.

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tionality of the contact suggests donation of electron density

from the O lone pair perpendicular to the plane of the sp2

carboxylate group. The charge density map calculated by DFT

methods (as specified in x2) on the isolated molecule supports

the possibility of this interaction (Fig. 2a). This interaction

defines a centrosymmetric supramolecular dimer (Fig. 2b). All

other short interactomic contacts would usually be interpreted

as weak CH� � �O interactions.

3.2. Periodic bond chain (PBC) analysis

The indexing of the macroscopic crystal morphology allows

verification of whether the shortest contacts correspond to

stronger interactions in a top–down approach (Bacchi et al.,

2011). In Fig. 3 the experimental indexing of the MI faces is

shown (a), associated with the corresponding contacts

between an incoming molecule and the growing crystal face

(b). Relevant faces are ð00�11Þ, being the largest, followed in

order of importance by (010) and ð10�22Þ, along with their

equivalents according to monoclinic symmetry. The relation

between outer shape and inner packing was investigated and

rationalized with the help of stereographic projections (Fig. 4)

according to the procedure outlined previously (Bacchi et al.,

2011). The experimentally visible faces (a) are reported on the

sphere (inset). The observed faces (hkl) (labelled in white) are

built by pairs of non-parallel arrays [uvw] (labelled in red) of

intermolecular interactions that actively contribute to the

crystal packing through periodic bond chains (PBC), and

whose orientations [uvw] may be identified by looking at the

stereographic projection of the observed faces (Fig. 4b).

Active PBCs should be represented by the [uvw] zone axes

(red arcs) corresponding to the directions that intersect at the

poles (hkl) of the faces observed experimentally (labelled in

black). In summary: we plot on the Wullf sphere all poles

representing the low-index faces (black dots in Fig. 4b); we

identify the experimentally visible faces (labelled in Fig. 4a);

we pick zone axes (red lines in Fig. 4b) that intersect at the

poles representing visible faces; these zone axes correspond to

the PBCs building up the faces.

The resulting PBCs for (1) are PBC1 = [010], PBC2 = [100],

PBC3 = [201], and the relation with the experimental crystal

faces is indicated at the top of Fig. 5. According to the

different development of the crystal along these directions, the

strength of the interactions along the PBC should be ranked as

PBC1 > PBC2 > PBC3, since the crystal shape is most elon-

gated along [010] and least along [201]. These directions can

be interpreted by looking at the intermolecular interactions

along the PBC directions in the crystal packing (Fig. 5). We

immediately note that the basic structural building units are

the centrosymmetric dimers shown in Fig. 2(b). These are

assembled along PBC1 and PBC2 by CH� � �O contacts invol-

ving the phenyl H atoms to give sheets that are stacked along

PBC3 with CH� � �O contacts involving methyl groups. This is

in agreement with the qualitative concept that aromatic CH is

a better hydrogen-bond donor than aliphatic CH.

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Acta Cryst. (2014). B70, 172–180 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline 175

Figure 3Experimental indexing of the MI faces (a); corresponding contactsbetween an incoming molecule and the growing face (b).

Figure 4Graphical determination of the [uvw] PBC vectors that span the observedfaces. (a) Face indices are represented with white labels; inset: position ofthe projection of the poles corresponding to the experimental faces. (b)Stereographic projection of the low-index faces (black dots). Experi-mental faces are labelled in black. The [uvw] vectors are represented bythe red zone arcs, labelled in red, square brackets. The same [uvw]directions are also labelled in (a), to show how the faces are built.

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3.3. Interaction energies for molecular dimers, trimers andtetramers

A parallel analysis has been carried out by computing

interaction energies based on the morphological considera-

tions. On the basis of the performed indexing, we chose the

most relevant crystal growth directions, considering that

generally the growth rate for the face is inversely proportional

to the surface area of each face (Prywer, 1995, 2001, 2002,

2003, 2004), i.e. the slower the growth, the larger the face

surface. On the other hand, the direction perpendicular to the

less developed face is the fastest direction of growth and

therefore the one bearing the most relevant intermolecular

interactions. Once the MI faces are selected, we cut the unit

cell for the crystal structure along those directions. It is useful

to recall that the choice of these directions was not made on

the basis of theoretical or speculative considerations, but on

the experimental evidence of crystal growth.

Now that we know along which directions to concentrate

our efforts, we analyse for each MI face the stability of

molecular dimers, trimers and tetramers. These were chosen

considering the architecture giving rise to the most stable

setup of aggregates, irrespective of any geometrical consid-

eration. Each successive monomer added to the previously

determined building block – i.e. a monomer added to another

monomer to generate a dimer, a monomer added to the

previously generated dimer to generate a trimer, and so on –

was identified by means of the symmetry operations required

to generate it. After having ranked the stability of the so-built

dimers, trimers and tetramers, we consider a slab of finite area,

corresponding to the environment of each MI face, and

simulate the attachment of a single molecule.

This approach allows us to confirm by DFT calculations

whether the energy involved in the growth process can be

predicted at the molecular stage (i.e. considering very simple

building blocks, when the crystal is already formed), by

attaching new units to the growing surface. The considered

geometries are the result of the molecular configuration and

relative arrangement of the crystal building blocks, as inferred

from the X-ray structure. The geometries were not optimized

in order to avoid any possible shift of the atomic positions. As

a result, the proposed examples are selected among real

experimental landscapes, and not among simulated ones. The

resulting interactions are reported in Table 2.

We start by analysing two possible interactions between

monomers as shown in Fig. 6, which correspond to the two

most stable dimers. In the first case (dimer 1) the two mono-

mers lie edge-on to each other, while in the second case (dimer

2) they form a face-to-face interaction. Taking the reference

unit as x; y; z, the first dimer corresponds to the interaction

with the molecule generated by the symmetry operator

x; y� 1; z, that is along the direction of PBC1 (Figs. 5 and 6,

top left), while the second dimer corresponds to the interac-

tion with the molecule generated by �x; 1 � y;�z (Figs. 5 and

6, top right). The second case is stabilized by �-stacking

interactions as reported in Table 3 and by the contact between

the electron-rich O atom of the NO2 group and the electron-

poor carboxylic sp2 C atom, as already suggested by the

geometrical analysis of the short interactions and by the

analysis of the molecular electron density. The relative ener-

gies of the two systems, calculated as explained in x2, are

reported in Table 4, where the most stable system, i.e. the one

with the lower energy, is considered to be zero. The signifi-

cantly greater stability of dimer 2 (> 41.9 kJ mol�1), which is

assembled head-to-tail, thus favouring dipole association,

could suggest a possible explanation for why the crystal-

lization yields a racemic mixture. Dimer 2 is centrosymmetric

and it gives rise to a characteristic crystal packing where the

basic building blocks are chains of dimers.

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176 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline Acta Cryst. (2014). B70, 172–180

Figure 5Ranking of the arrays of the main interactions (periodic bond chains, PBC) in the packing as derived by the analysis of the experimental morphology:chains of supramolecular dimers along PBC1 [010] and along PBC2 [001] build a sheet; the sheets are stacked along PBC3 [201].

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We analyse two different possible trimeric arrangements, as

reported in Table 4 and Fig. 6. Trimer 1, the most stable, is the

result of the attachment to dimer 1 of a molecule generated by

the operator x; yþ 1; z, corresponding to the arrangement

present in the (010) face when another molecule attaches on

this surface along PBC1. This confirms the suggestion of the

stereographic projection being the direction of fastest growth

of the crystal perpendicular to this face. A slightly higher

energy is calculated for trimer 2, generated by considering the

interaction along PBC2 of a molecule generated by 1 þ x; y; zto dimer 2, thus showing another �-stacking interaction (Table

3). This geometry resembles that present on the ð�1102Þ face,

which is actually a face of intermediate surface development

among the MI faces along PBC2, once again in agreement with

the information in the Wulff plot.

A similar approach can be applied to tetramers (Fig. 6), and

we have considered only three different tetramers repre-

sentative of the MI faces (see Table 4). Tetramer 1 is the most

stable and results from the attachment of a molecule gener-

ated by 1 � x; 2 � y;�z to trimer 1, approaching it from

below along PBC1. This is the growth direction of the (010)

face, and the picture could be interpreted as a description of

the possible crystal nucleation, where the original most stable

dimer is approached by new building blocks to give rise to fast

crystal growth along the PBC1 direction. Tetramer 2 is slightly

less stable, in spite of the already mentioned �-stacking

interactions (Table 3), as in dimer 2. It results from the

attachment of two molecules to dimer 2, one generated by

x� 1; y; z and another by 1 � x; 1 � y;�z. This is the direc-

tion of growth of the ð10�22Þ face along PBC2 [100], confirming

the overall face growth by means of the energy ranking. The

robustness of trimer 1 as the basic building unit is shown by

considering that tetramer 3, generated by the addition to

trimer 2 of a monomer along PBC1 (symmetry operator

x; y� 1; z) is less stable by far.

3.4. Interaction energies for molecules on crystal faces

After having performed the basic interaction analysis at the

molecular level, we extend our study by considering different

slabs of the crystal, corresponding to finite portions of the MI

faces. For this purpose, we first calculate the energy for the

single standalone monomer (Em), as in the previous case.

Then, after considering all of its interactions with a definite

slab representing the considered MI face, whose energy was

already calculated (Es), we compute the overall energy of the

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Acta Cryst. (2014). B70, 172–180 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline 177

Figure 6(a) The two most stable dimers as inferred by DFT calculations, corresponding to two experimental crystallographic landscapes; dimer 2 is the moststable. (b) The two most stable trimers; trimer 1 is the most stable. (c) The three most stable tetramers. The unit cell is represented to visualize theorientation of the supramolecular aggregates, with the a axis shown in red (along PBC2), b axis in green (along PBC1) and c axis in blue.

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system (Esm). We subtract Es from Esm in order to compare the

energy of the standalone monomer with the interacting one.

Furthermore, we compute the possible energy surplus by

defining �Em = Esm � Es � Em. In order to avoid any possible

inequality as a result of the different number of interactions

considered for a single monomer and, more critically, having

dealt with slabs containing different numbers of fragments, we

normalize these calculations for a single monomer (�Em/Ns).

The results obtained are reported in Table 5. They illustrate

the landscape more completely and clearly than in the

previous analysis which was confined to discrete numbers of

aggregates, and they confirm the results already obtained. In

summary: (010) has the greatest attachment energy Ea and this

is the smallest face but the fastest direction of growth; the

[010] direction, normal to this face, corresponds to PBC1

according to morphology considerations (see Fig. 4). The ð�1102Þface has the second largest Ea, and the morphological analysis

shown in Fig. 4 confirms that the growth direction [100]

normal to this face corresponds to PBC2. Finally, face (001)

has the smallest Ea, confirming that the direction normal to it,

[201], is the weakest periodic bond chain, i.e. PBC3.

Fig. 7 shows each considered slab, corresponding to each MI

face, together with the interacting monomer, and dashed in

yellow the shortest contacts already reported in Table 2.

3.5. Morphology prediction

The results obtained were compared with those inferred by

a morphology prediction, performed as described in x2. The

obtained crystal habit is provided in the supporting informa-

tion,1 together with a table reporting the computed MI faces.

Although the overall crystal shape is roughly confirmed as

expected (Punzo, 2011), the specific list of the MI faces is only

partially reproduced by the prediction. In fact, only the (001)

face [reported as (002)] is present, while the other MI faces are

not even reported as less important ones. These results suggest

that the standard (Punzo, 2013) forcefield-based approach to

morphology prediction is not completely reliable. As always,

the pitfalls of the theoretical predictions are not only due to

the chosen algorithms and forcefields, but more often to the

role of solvent. The calculations are carried out in vacuo, but

no more realistic results are achieved whether the solvent is

considered explicitly or not. However, arguments about the

role of the solvent can be interpreted as a potential tool for

fine tuning of the crystal habit.

All experimental attempts to use other solvents gave rise to

thinner crystals, such as in the case of a 1:1 mixture of n-

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178 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline Acta Cryst. (2014). B70, 172–180

Table 2Summary of short intermolecular contacts.

The third column gives the difference (�) with respect to the sum of the vander Waals radii (Bondi, 1964). Interactions are reported up to a maximum limitof � = 0.2 A. These values refer to positions inferred from the Fourier map ofthe reported crystal structure, and not optimized by means of the DFTcalculations. Interactions involving H atoms refer to X-ray positions, which are0.1–0.2 A shorter than nuclear positions.

Contact Distance (A) � (A)

O1� � �H3i 2.76 (2) 0.04O1� � �H6ii 2.72 (2) 0.00O1� � �H121iii 2.79 (4) 0.07O2� � �O4iv 3.2254 (19) 0.19O2� � �O7v 3.2117 (18) 0.17O2� � �C7v 3.325 (2) 0.11O2� � �C11v 3.211 (2) �0.01O2� � �H131v 2.83 (3) 0.11O4� � �O2iv 3.2254 (19) 0.19O4� � �H2iv 2.68 (2) �0.04O5� � �C9vi 3.266 (2) 0.05O5� � �C13vii 3.310 (3) 0.09O5� � �H9vi 2.38 (2) �0.34O6� � �H5viii 2.84 (2) 0.12O6� � �H121ix 2.73 (4) 0.01O6� � �H133x 2.72 (3) 0.00O7� � �H132vii 2.61 (3) �0.11O7� � �O2v 3.2117 (18) 0.17N2� � �H6viii 2.91 (2) 0.16C13� � �O5xi 3.310 (3) 0.09H2� � �O4xii 2.68 (2) �0.04H3� � �O1viii 2.76 (2) 0.04H5� � �O6i 2.84 (2) 0.12H6� � �N2i 2.91 (2) 0.16H6� � �O1ii 2.72 (2) 0.00H9� � �O5xiii 2.38 (2) �0.34H121� � �O6xiv 2.73 (4) 0.01H121� � �O1iii 2.79 (4) 0.07H131� � �O2v 2.83 (3) 0.11H132� � �O7xi 2.61 (3) �0.11H133� � �O6vii 2.72 (3) 0.00

Symmetry codes: (i) x;�1 þ y; z; (ii) �x;�y;�z; (iii) 1 � x;�y;�z; (iv)1 � x; 1 � y;�z; (v) �x; 1 � y;�z; (vi) 1 � x;� 1

2 þ y; 12 � z; (vii) �x;� 1

2 þ y; 12 � z;

(viii) x; 1 þ y; z; (ix) �1 þ x; 1 þ y; z; (x) �x; 12 þ y; 1 � z; (xi) �x; 1

2 þ y; 12 � z; (xii)

1 � x; 1 � y; z; (xiii) 1 � x; 12 þ y; 1

2 � z; (xiv) 1 þ x;�1 þ y; z.

Table 3Selected �–� stacking interactions between aromatic rings (C1–C6) in(1).

Centroid� � �centroid Distance (A) Interplanar angle (�)

Cg� � �Cgi 3.8647 (9) 0Cg� � �Cgii 3.8863 (9) 0

Symmetry codes: (i) �x; 1 � y;�z; (ii) 1 � x; 1 � y;�z.

Table 4Energy ranking for dimers, trimers and tetramers.

In each case, the most stable aggregate is considered to be zero.

Supramolecular clusters and symmetrygenerators Energy (kJ mol�1)

Dimer 1 [(x; y; z); (x; y� 1; z)] 45.135Dimer 2 [(x; y; z); (�x; 1 � y;�z)] 0.000

Trimer 1 [(x; y; z); (�x; 1 � y;�z);(x; yþ 1; z)]

0.000

Trimer 2 [(x; y; z); (�x; 1 � y;�z);(1 � x; 1 � y;�z)]

4.961

Tetramer 1 [(x; y; z); (�x; 1 � y;�z);(x; y� 1; z); (1 � x; 2 � y;�z)]

0.000

Tetramer 2 [(x; y; z); (�x; 1 � y;�z);(1 � x; 1 � y;�z); (x� 1; y; z)]

12.142

Tetramer 3 [(x; y; z); (�x; 1 � y;�z);(1 � x; 1 � y;�z); (x; y� 1; z)]

27.059

1 Supporting information for this paper is available from the IUCr electronicarchives (Reference: BI5027).

electronic reprint

hexane and benzene. This feature can be related to an even

faster growth along the PBC1 direction perpendicular to the

(010) face. As a consequence, we can assume that the presence

of a fraction of a different solvent allows further stabilization

in terms of Ea, thus speeding up the crystal growth along that

face. This should be due to an even weaker interaction by n-

hexane molecules with those cropping out from the (010) face.

A possible interpretation could be the diminished possibility

of �-stacking interactions, which can be offered by benzene

and not by n-hexane, which could influence the crystal growth

relative to that in pure benzene solution, thus altering the final

habit.

4. Conclusions

The experimental indexing, being directly related to the

evidence observed, is in principle more reliable than a

computationally inferred crystal morphology. The algorithms

used for morphology prediction have a well known tendency

to overestimate the amount and relative percentage of the MI

faces (Punzo, 2011; Lazo Fraga et al., 2013; Punzo, 2013). This

is proved by the results of our morphology prediction (in the

supporting information) which confirm, in principle, the

landscape inferred by the experimental measurements, but

predict the existence of some less relevant MI faces in the

apical part of the crystal which were not actually present in the

real sample. The demonstrated computational analysis, on the

other hand, provides a complete picture of the key interac-

tions in the crystal. It is based on, and driven by, the experi-

mental morphological inspection, and allows more specific

considerations about the coopera-

tive role of all of the considered

non-covalent interactions,

compared with the traditional

analysis of a crystal structure. The

present study shows that, starting

from the macroscopic observation

of the crystal, we can considerably

aid the crystal engineering

approach. Instead of relying on

purely speculative considerations,

our analysis is guided at the mole-

cular level on the basis of the real

experimental crystal growth.

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Acta Cryst. (2014). B70, 172–180 Giuseppe M. Lombardo et al. � Racemic �2-isoxazoline 179

Table 5Energy ranking of the interactions between a single molecule and the slab corresponding to eachconsidered MI face.

Values are reported in Hartree, to avoid being flattered by the use of the scientific notation and then convertedat the end of the table, in bold, to kJ mol�1 (1 Hartree = 2627.255 kJ mol�1).

Em

(Hartree) Ns

Millerindices

Es

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(Hartree)�Em/Ns

(kJ mol�1)

�1138.2302 6 001 �6829.5705 �7967.83555 �1138.26505 �0.03485089 �15.23567 010 �7967.76347 �9106.05451 �1138.29104 �0.06083542 �22.79586 10�22 �6829.55645 �7967.83112 �1138.27467 �0.04447011 �19.4408

Figure 7(a) ð001Þ, (b) ð10�22Þ and (c) ð010Þ slabs corresponding to each MI face with each incoming monomer.Dashed yellow lines are the shortest contacts reported in Table 2.

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