Cocrystals: Solution, Mechanochemistry, and Sublimation

Article abstract of DOI:10.1021/acs.cgd.9b01450

A systematic study of the effect of crystallization method on the resulting solid-state form of a series of organic cocrystals has been carried out. Cocrystals of p-benzoquinone (BQ) and one of four monosubstituted p-halophenols were made by crystallization from chloroform, cosublimation in vacuo, and neat grinding. Cocrystals with both 1:1 and 2:1 donor-acceptor ratios can be prepared from all four BQ-halophenol combinations. Here we report the preparation of four new cocrystals of BQ with either 4-fluorophenol or 4-iodophenol. In the case of the 1:1 4-fluorophenol-BQ cocrystal, different polymorphs were isolated by recrystallization from solution and cosublimation. Sublimation is shown to be an important technique in accessing the phase space of cocrystals.

Full text of DOI:10.1021/acs.cgd.9b01450

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Article
Co-crystals: solution, mechanochemistry and sublimation
Thalia Carstens, Delia A. Haynes, and Vincent J. Smith
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b01450 • Publication Date (Web): 27 Dec 2019
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Co-crystals: solution, mechanochemistry and sublimation.
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Thalia Carstensa, Delia A. Haynesa and Vincent J. Smithb*
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a. Department of Chemistry and Polymer Science, Stellenbosch University, P. Bag X1,
Matieland, Stellenbosch, 7602, South Africa.
b. Department of Chemistry, Rhodes University, PO Box 94, Grahamstown, 6140, South Africa.
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Abstract
A systematic study of the effect of crystallization method on the resulting solid-state form of a series
of organic co-crystals has been carried out. Co-crystals of p-benzoquinone (BQ) and one of four
monosubstituted p-halophenols were made by crystallization from chloroform, co-sublimation in
vacuo, and neat grinding. Co-crystals with both 1:1 and 2:1 donor-acceptor ratios can be prepared
from all four BQ-halophenol combinations. Here we report the preparation of four new co-crystals of
BQ with either 4-fluorophenol or 4-iodophenol. In the case of the 1:1 4-fluorophenol-BQ co-crystal,
different polymorphs were isolated by recrystallization from solution and co-sublimation. Sublimation
is shown to be an important technique in accessing the phase space of co-crystals.
Introduction
The physicochemical properties of solid (crystalline) materials are strongly dependent on how the
atoms, ions or molecules that make up these materials arrange in the solid state. Since X-ray diffraction
(powder and single-crystal), thermal analysis and spectroscopy are still our most important methods
for characterizing the solid state, it is important to produce crystalline materials of high quality suitable
for these methods.1,2 Of higher importance still is the discovery and characterization of new solid
phases such as polymorphs, co-crystals, solid solutions and various other crystalline forms.
Polymorphism is of particular interest to pharmaceutical chemists,3–6 in non-linear optics,7,8 for
molecular electronics9–12 and in many other areas. The different packing arrangements of polymorphs
are usually associated with differences in intermolecular interactions, which often result in different
bulk properties. In general, the importance of intermolecular interactions in the occurrence of new
phases cannot be understated, especially for systems such as co-crystals. Co-crystals are an alternative
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to polymorphism for phase modification, and for the generation of physical and chemical properties
which differ from those of the starting materials.13 Co-crystals are essentially crystalline single-phase
materials made up of two or more different molecules in a stoichiometric ratio.14 Co-crystallization has
become a preferred method for altering the bulk properties of compounds since the effects of co-
crystallization can be quite pronounced.15 Co-crystallization is facilitated by taking advantage of the
inherent directionality and selectivity of many noncovalent interactions.16 However, even a deep
understanding of these structure-directing interactions does not always result in successful co-
crystallization; in other words, whether or not a particular co-crystal will form under certain
experimental conditions is not predictable.17,18 Many factors, both physical and chemical, contribute
to successful co-crystal formation and it is rather unsurprising that the method of preparation has
some impact on the outcome of a co-crystallization experiment.19–21 It is for this reason that crystal
growth techniques are constantly being discovered, modified and refined in order to access new phase
space.
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Crystal growth by recrystallization from solution remains the most common approach, but a
number of other methods have come to the fore.22 These methods include melt recrystallization,23
vacuum24 and in-air sublimation,25 crystallization in micro-emulsion droplets,26 crystallization in small
molecule organogels27 and so forth. Mechanochemical methods (both neat and liquid assisted
grinding) are also used to access new phases, even though the products of these methods are usually
polycrystalline and require further processing in order to obtain single crystals for X-ray diffraction.28
Growing single crystals by sublimation is still comparatively unexplored, even though almost
two thirds of all pure organic compounds sublime.29 However, this method has several advantages: it
greatly simplifies separating out impurities, is easily tuneable, fast and can produce diffraction-quality
crystals. Moreover, sublimation eliminates the need for solvent considerations and allows for the
molecules of interest to interact directly with each other.30 As with any crystallization process, new
solid-state forms may be isolated during sublimation, such as apohost phases, polymorphs, gas-solid
inclusion complexes and even co-crystals.2,30–37
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Preparing co-crystals by the co-sublimation of two or more different molecules was initially
considered a difficult task owing to the possibility that the individual components may exert very
different vapour pressures and would therefore have very different sublimation temperatures.
However, with a suitably well-designed apparatus this hindrance can easily be overcome.32
Furthermore, the literature with respect to co-sublimation is rather sparse with only limited accounts
on this topic.2,13,18,24
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In this work, we have investigated the formation of co-crystals between p-benzoquinone (BQ)
and four different halophenol co-formers by co-sublimation, along with other more common
crystallization methods. We aimed to establish whether these co-crystals could be produced by
sublimation, and if the forms obtained would be the same as that obtained using solution
crystallization or mechanochemistry. We therefore carried out a systematic investigation of the effect
of crystallization method on stochiomorphic and polymorphic variation in the BQ-halophenol system.
The choice of BQ as the primary molecule in this investigation is because BQ is known to readily co-
crystallize with a variety of small organic molecules such as bis--naphthols,38–41 and it easily sublimes.
Owing to its high vapor pressure, co-crystals with BQ are known to readily form simply by being in
contact with a co-former, and without grinding. Kuroda et al.42 have termed this phenomenon co-
crystallization through ‘molecular diffusion’. Co-crystal formation by molecular diffusion is known to
be a slow process, and mechanochemical grinding speeds up this process. However, since these co-
crystals form by diffusion through the vapour phase, we hypothesized that co-crystallization by co-
sublimation of the components would be an effective and potentially faster method of forming
multicomponent materials with BQ.
In 1967, Shipley et al. reported the synthesis of four co-crystals formed between BQ, the
common component, and 4-chlorophenol (ClP) or 4-bromophenol (BrP) as the accompanying co-
former.43,44 Each combination has both a 1:1 and a 2:1 stoichiometric form (stoichiomorphs). The 1:1
{BrP}{BQ} and {ClP}{BQ}i co-crystals are isostructural to one another, as are the 2:1 forms. We decided
i Curly brackets indicate co-crystals.
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to investigate co-crystallization by sublimation using the Shipley et al. series, while also completing the
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set by using all four halophenols.
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Results and Discussion
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In this study, three methods for preparing co-crystals of BQ and four p-halophenols were investigated:
i) mechanochemical neat grinding using a mortar and pestle, ii) recrystallization from solution (ex
chloroform) and, iii) co-sublimation. In order to create a sublimation environment that is tuned to the
properties of each co-former, a co-sublimation apparatus was designed to allow for co-crystallization
using this method. The two co-formers (BQ and a halophenol) are heated and sublimed at different
temperatures. Both components are driven into the gas phase simultaneously, crystallizing in the
upper (cooler) parts of the apparatus, affording a degree of control over the co-sublimation
environment (conditions). Details of this apparatus, and of all crystallization methods, are given in the
experimental section (see also Figure S1, ESI). Nine co-crystal forms were characterized in this system
and are summarized in Figure 1.
To allow for appropriate comparison, co-crystals prepared by Shipley et al.50,51 were also
prepared using the same methods as previously reported, and X-ray diffraction data were re-collected.
We observed interesting spectroscopic behavior upon formation of the co-crystals in the form of a
distinct color change. According to Shipley et al.50,51 these co-crystals are charge transfer complexes
and the observed color changes are evidence thereof. The 4-halophenols (HP) are the charge donor
molecules (CD) and BQ is the charge acceptor molecule (CA). Two different co-crystal stoichiometries
were observed (1:1 and 2:1 CD:CA ratios) as bright orange- and deep red-colored crystals, respectively.
In this text, co-crystals with 1:1 ratios are denoted by the co-crystal code followed by the letter a, while
the 2:1 co-crystals are indicated by the letter b (Fig. 1).
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Figure 1. A summary of the products obtained when the 4-halophenols are reacted with p-benzoquinone to yield co-crystals.
Co-crystals with a 1:1 stoichiometry (halophenol:benzoquinone) are denoted by the letter “a”, whereas co-crystals with 2:1
stoichiometries are represented with the letter “b”. Co-crystals 2a/b and 3a/b have been previously reported. 1a has two
polymorphs.
As mentioned above, the co-crystals investigated in this work are charge transfer materials, as
indicated by the colour of the co-crystals (red, orange, yellow). In reported studies on similar
materials,45–47 the charge donor molecule is often kept constant while the charge acceptor molecule is
halogenated to observe what effect the electron-withdrawing halogen substituents would have on the
structure and electronic properties of the resulting material. In this study, we vary the halogen
substituent on the charge donor while keeping the charge acceptor molecule constant. The degree of
charge transfer is expected to be rather low in these materials, due to the halogen substituents on the
donor atoms decreasing the donor ability of the 4-halophenols. Since these co-crystals were not
prepared to investigate their potential as charge-transfer complexes, but rather to investigate the
efficacy of co-sublimation in a new apparatus and structural differences resulting from the halogen
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substituent or crystallization conditions, the degree of charge transfer in these materials has not been
quantified, but see Table S3 in the ESI for calculated HOMO/LUMO energies.
The effect of crystallization method on the stoichiomorphic and polymorphic form of the co-
crystal is discussed below, followed by a description of the crystal structures of the nine co-crystal
forms obtained.
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Effect of crystallization method
Reaction of a particular halophenol with benzoquinone yielded both 1:1 (a) and 2:1 (b) co-crystals for
all four halophenols (stoichiometries are given as halophenol:benzoquinone) (Fig. 1).
Solution crystallization
Recrystallization of a pre-ground powderii from solution yielded either the 1:1 or the 2:1 form
exclusively, depending on the stoichiometry of the starting materials used. This is true for all cases
except the {IP}{BQ} co-crystal, which exclusively yielded crystals of the 2:1 form from solution
recrystallization.
Crystallization by sublimation
Sublimation, using our in-house designed apparatus (Fig. S1), yielded 1:1 and 2:1 forms
simultaneously, independent of the ratio of starting materials. The two stoichiomorphs crystallize
separately in different parts of the sublimation apparatus, presumably due to the difference in
sublimation temperatures of the co-crystals themselves, which leads to the different forms crystallizing
at different temperatures: the 1:1 form always crystallized in the cooler parts of the apparatus. The
exception to this is the IP-BQ combination, which only gave a 1:1 form from sublimation. In other
words, an exact molar ratio of co-formers is not a requirement to form these co-crystals by
sublimation; co-crystals with both stoichiometries will form even when there is an excess of one co-
former. This is not an uncommon observation for the formation of co-crystals,48,49 however it makes
ii Attempts to produce co-crystals by dissolving the starting materials together without pre-grinding only
yielded crystals of the respective starting materials.
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an interesting contrast to solution crystallization, where the stochiomorphic form obtained depends
on the ratio of starting materials.
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Co-crystal 1a is polymorphic, with solution crystallization and sublimation yielding different
forms. The polymorph obtained from solution is designated the -phase (-1a), while the form
obtained from sublimation is the -phase (-1a).
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Mechanochemistry
Both 1:1 and 2:1 forms could also be prepared mechanochemically in most cases (see ESI for
details). In the case of ClP and BrP, the co-crystal obtained mechanochemically is the same form as
that obtained from both solution crystallisation and co-sublimation, and is dependent on the ratio of
the starting materials. For FP, -1a, the polymorph obtained from sublimation, is also obtained from a
1:1 grind while a 2:1 grind yields 1b. A 1:1 grind of IP and BQ yields 4a, which can also be obtained
from sublimation.
Mechanochemical experiments indicated the existence of a potentially extremely short-lived
additional phase of co-crystal 4 (Fig. 2). On commencing the grinding experiment, an orange powder
forms almost immediately. However, within seconds and without sufficient time to characterise the
material that forms, the powder converts to a deep coral red colour, shown to be the 1:1 co-crystal 4a
(Fig. S8).
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The stoichiometry of the co-crystal forms can be interchanged repeatedly using
mechanochemistry, which simply requires adding a molar equivalent of the relevant co-former and
grinding (Figures S2-S8). For example, 2a can be converted to 2b by adding a molar equivalent of ClP
followed by grinding the sample; 2b can then be converted to 2a by adding a molar equivalent of BQ,
and this can be done repeatedly. This is not the first report of such a phenomenon; however, it is still
quite rare in the field of mechanochemistry and solid state reactions.50–52
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Figure 2. Neat grinding of 4-iodophenol and benzoquinone together to form 4a. Left: Short-lived form of co-crystal 4 (orange),
Right: the 1:1 form, co-crystal 4a.
In order to further investigate the polymorphs of 1a, we used liquid-assisted grinding (LAG).
Co-crystal 1a has two polymorphic forms; -1a is the major product from neat grinding using a mortar
and pestle. We investigated the effects of LAG with chloroform using both a mortar and pestle and a
ball mill to determine whether either the addition of solvent or the change in grinding conditions would
yield α-1a. In both instances, identical PXRD patterns were obtained; demonstrating no change from
the product obtained using neat grinding (Fig. S14). However, we were unable to identify
unambiguously the form obtained after conversion to 1b and its subsequent reaction to reform the
1:1 form. Furthermore, this form persists for all subsequent interconversions (Fig. S2). Differential
Scanning Calorimetry also showed no evidence for conversion between the two polymorphs (Fig. S14-
15).
Crystal structures
The unit cell and space group information for the nine co-crystal forms discussed in this work are given
in Table 1 (for complete crystallographic data see Table S1). Hydrogen bond parameters are reported
in the Supplementary Information (Table S2).
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Table 1. Unit cell parameters for the co-crystals discussed in this work.
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Unit
cell
1b
2a
100(2)
P
2b
3a
100(2)
P
3b
4a
4b
-1a
293(2)
P1
-1a
100(2)
Pc
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7
T (K)
100(2)
P21/c
100(2)
P21/c
100(2)
P21/c
100(2)
P21/c
100(2)
P21/n
Space
group
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a (Å)
b (Å)
c (Å)
/°
3.606(4)
6.446(8)
11.35(1)
91.77(2)
98.42(2)
102.19(2)
3.8460(2)
6.390(2)
22.184(1)
11.0335(7)
5.9058(4)
11.4954(7)
6.8353(4)
7.0972(4)
12.2879(7)
93.639(2)
106.001(2)
112.347(2)
11.6009(7)
6.0460(3)
11.7339(7)
6.8467(5)
7.117(5)
11.8101(4)
6.0966(2)
11.8626(4)
11.6713(4)
10.3145(4)
9.4247(2)
10.807(2)
6.1013(12)
27.325(5)
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12.5065(9)
94.746(2)
104.692(2)
112.515(2)
/°
90.478(2)
481.10(4)
98.597(2)
740.64(8)
96.987(2)
816.89(8)
96.849(1)
848.03(5)
92.901(1)
92.846(2)
1799.5(6)
/°
V (Å3)
254.5(5)
520.40(5)
533.41(7)
1133.13(7)
Co-crystals with 1:1 stoichiometry
1a
Two different methods of crystallization, solution crystallization and sublimation, yielded two
different polymorphs of 1a, -1a and -1a. The -phase, obtained by crystallization from chloroform,
crystallizes in the triclinic space group P1. The asymmetric unit of -1a consists of a single molecule
each of both BQ and FP. The molecules form a 1:1 hydrogen-bonded dimer through O-H···O hydrogen
bonds that are 2.761(7) Å in length (donor-acceptor) with a bond angle of 171(1)°. The dimers stack in
an offset manner to form columns down the a axis. The intra-stack distance, measured as the distance
between the planes of the FP rings, is 3.606(6) Å. Columns of dimers are connected by two different
푅22(8)
types of
hydrogen-bonded rings – one between two BQ molecules, involving only C=O as
hydrogen-bond acceptor, and another between two fluorophenol molecules, with fluorine and
C-OH as H-bond acceptors (Fig. 3a).48 The resulting three-dimensional packing arrangement is polar
(Fig. 3b).
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Figure 3. Packing in α-1a. (a) Hydrogen bonding between two BQ molecules as well as two FP units in α-1a. (b) Polar
packing arrangement of α-1a viewed down the a axis.
Co-sublimation of FP and BQ results in a second polymorph, -1a, which crystallizes in the
monoclinic space group Pc. The asymmetric unit of this polymorph contains one molecule of BQ and
one molecule of FP, which are hydrogen bonded to each other forming a hydrogen bonded dimer
similar to -1a. The O-H···O hydrogen bond (D···A) distance is 2.741(5) Å and the bond angle is 177(6)°.
However, the dimeric units, which stack in offset columns along c are also inclined by 62.5° relative to
each other (Fig. 4). The intra-stack distance (centroid-to-centroid) is 3.846(3) Å while consecutive
stacks are linked by C-F···H interactions.
IR spectroscopy gives some insight into the intermolecular interactions in β-1a compared to
those in α-1a and BQ (Figures S20-22). Both the hydrogen bond stretches as well as the C-F bond
stretch show a clear shift to lower frequencies from α-1a to β-1a. This indicates a strengthening of the
hydrogen bonding and C-F···X (X = H, O) interactions in the structure of β-1a when compared to those
in α-1a.
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Figure 4. (a) The hydrogen bonding scheme of β-1a. (b) The packing arrangement of β-1a viewed down the a axis.
2a and 3a
The crystal structures of the 1:1 co-crystals formed between ClP/BrP and BQ have been described by
Shipley and Wallwork.43 The main features of these structures are highlighted here, to facilitate
comparison with the new structures reported in the current study.
The co-crystals 2a (ClP·BQ, CSD refcode BNQCLP) and 3a (BrP·BQ, CSD refcode BNQBRP)
crystallize in the triclinic space group P, and are isostructural to one another. The BQ and ClP/BrP
molecules form hydrogen-bonded dimers, which stack along the b axis such that BQ and HP molecules
alternate in the stack (Fig. 5). Stacks pack alongside one another along a such that BQ and HP are
adjacent along the 100 direction. Along the c axis, stacks are packed alongside one another in a slipped
fashion. Short contacts (Br···O, 3.170(1) Å; C-Br-O, 160.61(4)°) propagate through the structure of 3a,
alongside hydrogen bonding, to form infinite chains of alternating hydrogen and halogen bonds that
are parallel to the ac plane (Fig. 5). Similar halogen-bonding contacts are observed for the isostructural
co-crystal 2a, however the contacts are longer (3.2854(9) Å) and marginally less linear (C-Cl-O
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157.46(4)°), indicating a weaker halogen bond. This is not uncommon for halogen bonds involving
chlorineiii53
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Figure 5. Hydrogen and halogen bonding motifs for 2a (a) and 3a (c). Infinite chains of alternating hydrogen (H) and halogen
(X) bonds, propagating along the c axis in co-crystals 2a (b) and 3a (d). Both the hydrogen and halogen bonds are displayed
as red dotted lines.
4a
Co-crystal 4a crystallizes in the monoclinic space group P21/c. The asymmetric unit consists of two half
molecules of BQ and one molecule of 4-iodophenol, which form a hydrogen-bonded trimer. The
iii Atomic radii used here for the determination of the potential presence of halogen bonding interactions are as
published by A. Bondi64, in particular the atomic radii of halogens as substituents to phenyl rings. The atomic
radius of a halogen atom appears to increase slightly when bonded to a phenyl ring.
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molecules are arranged in alternating stacks or columns parallel to the ac diagonal. The structure has
a single layer of BQ molecules that separate consecutive hydrogen-bonded units from one another
(Fig. 6). The BQ layers are held in place by I···O halogen bonds at both carbonyl moieties on the BQ
molecule. Thus, an infinite hydrogen- and halogen-bonded chain propagates through the structure.
The OH···O contact distances in the trimer are 2.749(3) Å, which are in the same range as that of both
1a co-crystals, albeit slightly longer than the H-bonding distances in co-crystals 2a and 3a.
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Figure 6. View of 4a down the a axis showing the columns of 2:1 H-bonded trimers separated by a single column of
p-benzoquinone (highlighted in blue). OH···O hydrogen-bonded contacts and CO···I halogen bonding contacts are shown as
red dotted lines.
Co-crystals with 2:1 stoichiometry
1b, 2b and 3b
Co-crystals 1b, 2b and 3b, the latter pair previously reported by Shipley and Wallwork,50 are
isostructural to one another, crystallizing in the monoclinic space group P21/c. In each case the
asymmetric unit contains half a molecule of BQ and a molecule of 4-halophenol (halo = F, Cl and Br),
which are hydrogen bonded together to form a trimer. Within each hydrogen-bonded unit of 1b,
OH···O contacts are 2.741(1) Å in length, which is slightly longer than those observed in the structures
of 2b and 3b (2.7258(17) and 2.7194(15) Å respectively). In each case the trimers are arranged in
slipped stacks, such that the hydroxyl moiety (C–O(H)) of the 4-halophenol molecules in one trimer are
positioned over the center of a BQ ring in the trimer below (C-O(H)···π 3.028 Å for 1b, C-O(H)···π 3.070
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Å for 2b and C-O(H)···π 3.083 Å for 3b), typical of a lone pair···π interaction. Similarly, the carbonyl
moiety of BQ is located over the center of a 4-halophenol ring in the trimer below (C=O···π 3.164 Å for
1b, C=O···π 3.319 Å for 2b, and C=O···π 3.417 Å for 3b). Consecutive layers down the c axis have a
crisscrossed appearance when viewed down c (Fig. 7). The crisscrossed stacks/layers pack alongside
one another along the a direction and are interleaved by the halogen atoms.
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Figure 7. View of 1b, 2b and 3b down the c axis. This view is edge-on to the hydrogen-bonded trimers. Blue and green colors
are used to highlight crisscrossed stacks.
An overlay of the crystal structures of 1b, 2b and 3b confirms that they are isostructural (Fig. 8 and
Table 1).
Figure 8. Structural overlay (Mercury 3.10.3)54,55 of 1b (green), 2b (yellow) and 3b (blue) viewed down the b axis, highlighting
the similarity of the packing arrangements.
4b
The asymmetric unit of 4b consists of a molecule of BQ and two molecules of IP, which form a hydrogen
bonded trimer analogous to those seen in the other 2:1 co-crystals. However, the IP molecules are not
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symmetry related, as in the other 2:1 forms, having OH···O contact distances of 2.719(2) and 2.770(3)
Å. The shorter OH···O distance results from an out-of-plane rotation (mean plane through the central
BQ molecule) of an IP molecule and the longer OH···O distance is owing to an
in-plane rotation (mean plane through the central BQ molecule) of the second IP molecule (Fig. 9a).
The rotations of the IP molecules occur to accommodate the size of the iodine atoms and the strength
of the iodine-iodine interactions. The absence of crystallographic symmetry between the two IP
molecules (either side of BQ) results in a doubling of the unit cell along the c axis (Fig. 10 bottom right),
when compared to the other 2:1 forms. As with 1b, 2b and 3b, the hydrogen bonded trimers in 4b
form slipped stacks, which pack alongside one another in a crisscrossed fashion. The larger size of the
iodine atoms (compared to the other halogens) result in the hydrogen-bonded trimers in 4b being
rotated such that they are no longer edge-on (Fig. 9b).
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Figure 9. a) An overlay of the hydrogen bonded units of 1b (green) and 4b (purple) viewed in different orientations (top and
bottom). The distortion in the trimer in 4b is clear. b) Type II halogen bonding between iodine molecules (purple) in 4b. The
distortion of the trimers away from the plane is highlighted in the packing diagram on the right, where I···I contacts are shown
in purple.
Unlike the other 2:1 forms, the structure of 4b contains short I···I interactions (Fig. 9b). One of
the 4-iodophenol molecules is involved in Type II halogen bonding56 with an iodine atom belonging to
an iodophenol molecule in an adjacent layer. The extensive Type II I···I halogen-bonding interactions
present in this structure appear to be responsible for the distortion of the hydrogen-bonded units (as
mentioned previously). The size of the iodine atoms as well as the different iodine environments result
in 4b not being isostructural to the other 2:1 co-crystals, despite the packing arrangements being very
closely related (Fig. 10).
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Figure 10. The space fill packing arrangement of the 2:1 co-crystal forms: 3b (top left), 2b (top right), 1b (bottom left) and 4b
(bottom right). The packing arrangement in 4b shows two environments for iodine resulting in a doubled c axis.
Summary
The results of this systematic study, summarised in Scheme 1, confirm that by simply applying
a different crystallization technique, different solid forms may be obtained from the same molecular
components. This emphasises the importance of varying crystallization methods and techniques when
screening for potential solid forms of a material.
Scheme 1. Summary of the results obtained when using different methods to crystallize co-crystals of benzoquinone and the
p-halophenols. In the case of 2a, 3a, 1b, 2b and 3b (highlighted by green boxes), recrystallization from solution, sublimation
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and neat grinding yields the same crystal form, with the result dependent only on the stoichiometry of the starting materials.
Co-crystal 1a is polymorphic, and recrystallization yields the α-phase (red) whereas sublimation yields the -phase (purple).
For combination 4, the 1:1 form 4a was obtained from sublimation and neat grinding (blue boxes), whereas recrystallization
from solution yields only the 2:1 form 4b (black).
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Unique to this study is the systematic investigation of the use of sublimation to grow crystals.
We successfully, and with some measure of control, produced co-crystals using an in-house built co-
sublimation apparatus of simple design. We were able to grow crystals of different stoichiometries at
the same time in the same apparatus, but, significantly, in such a way that the different forms are
easily separable after crystal growth.
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It is particularly noteworthy that when different forms are obtained from solution
recrystallization and mechanochemistry (the polymorphs of 1a and stoichiomorphs 4a/4b), the form
obtained from sublimation is the same as that obtained mechanochemically.
Conclusions
It is well established that different crystallization methods may yield different solid forms of a material,
which is an important consideration in many fields. This systematic study of co-crystals formed
between benzoquinone and the p-halophenols strengthens this observation. Recrystallization from
solution and mechanochemical synthesis gave different solid-state forms for both the
fluorophenol/benzoquinone and the iodophenol/benzoquinone systems. Additionally, we found that
sublimation yields the same form as the mechanochemical method. This may prove to be a useful
technique to obtain single crystals of solid forms previously only accessible by mechanochemistry.
Sublimation, in our opinion, is an underutilized crystal growth method and these results reveal that
there is room for further investigation.
Finally, the sublimation apparatus developed for this study proved to be a fast and effective
route to make multicomponent crystals, with control over the sublimation environment for each
component. Stoichiomorphs were obtained simultaneously and in such a way that they could be easily
separated. It is clear from the work presented here that sublimation should be more widely employed
as a means to access new parts of solid-state phase space.
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Experimental
Co-formers p-benzoquinone (BQ), 4-fluorophenol (FP), 4-chlorophenol (ClP), 4-bromophenol (BrP) and
4-iodophenol (IP) were purchased from Sigma Aldrich and used without further purification. Three
different crystallization techniques were used to produce co-crystals.
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Solution crystallization. All co-crystals were prepared from solution using the same general
methodology. Details of the preparation of 1a (1:1 form) and 1b (2:1 form) are given as representative
procedures.
p-Benzoquinone (10 mg, 1 eq.) and 4-fluorophenol (11 mg, 1 eq.) were ground together until
a color change was visible. The resulting powder was dissolved in chloroform (3-5 ml) and allowed to
crystallize in the refrigerator at 4 C, yielding orange rods and plates of the alpha form of 1a (-1a).
The same procedure was followed for the synthesis of 1b: 4-fluorophenol (22 mg 2 eq.) was ground
together with BQ (10 mg, 1 eq.), the powder dissolved in chloroform and the resulting solution allowed
to crystallize in the refrigerator. Orange rods and plates (-1a) or deep red needles (1b) of diffraction
quality were obtained after 2-3 weeks. Crystals were repeatedly harvested as the solvent evaporated.
Co-crystals of BQ with 4-chlorophenol (2a and 2b), 4-bromophenol (3a and 3b) and 4-
iodophenol (4b) were obtained from solution in the same manner. Three halophenols yielded both a
1:1 (a) and 2:1 (b) form from the appropriate solution. However the 4-iodophenol/BQ combination
yielded only a 2:1 form, even from crystallization experiments containing a 1:1 molar ratio of co-
formers. All 1:1 co-crystals were observed to have the same color and morphology, orange rods and
plates, where all the 2:1 co-crystals were deep red needles. The methodology described here gave the
same forms for 2a/b and 3a/b as reported previously by Shipley and Wallwork,43,44 and yielded the 2:1
form, 4b.
All attempts to prepare co-crystals by dissolving the components in chloroform without prior
grinding were unsuccessful, resulting in isolation of crystals of the coformers.
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Table 2. Details of conditions used to form co-crystals by sublimation as well as mechanochemical methods, using
benzoquinone and a halophenol. Numbers in brackets indicate the relative equivalents of halophenol. Temperature is that
used in sublimation experiments.
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Co-former
Mass (mg)
10
11(1), 22(2)
11.7(1), 23.4(2)
16.5(1), 33(2)
20(1), 40(2)
Temperature ( °C)
p-benzoquinone
4-fluorophenol
4-chlorophenol
4-bromophenol
4-iodophenol
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Sublimation. Co-crystals were also grown by co-sublimation under vacuum using an in-house designed
apparatus containing two bulbs that can be heated to different temperatures under reduced pressure
(see ESI for a detailed description of the apparatus).
The beta phase of co-crystal 1a (-1a) and co-crystal 1b were synthesized concomitantly by
adding BQ (10 mg, 1 eq.) and either 1 or 2 equivalents of FP (see Table 2) separately to the two sample
chambers of the sublimation apparatus. Each component was heated to the temperature specified in
Table 2, whist the apparatus was kept under a dynamic vacuum of 14 mbar. Crystals of -1a and 1b
were isolated from the glass wall inside the chamber. Unreacted starting material remained in the
sample bulbs and did not crystallize on the walls of the sublimation apparatus.
The same procedure was followed for the synthesis of co-crystals 2a/b, 3a/b and 4a. Quantities
and sublimation temperatures are given in Table 2. Diffraction-quality crystals formed on the walls of
the glass tube after a few minutes in the case of combinations 1-3, and overnight in the case of co-
crystal 4a. For co-crystal combinations 1-3, the 1:1 and 2:1 co-crystals grew concomitantly,
independent of the starting ratio of co-formers. In all cases where the 1:1 and 2:1 forms grew at the
same time, we observed that the 1:1 form crystallized closer to the U-bend of the apparatus where
the glass wall is cooler, whereas the 2:1 form always crystallized on the warmer areas of the glass wall.
The polymorphs -1a and -1a appear to be morphologically identical, both crystallizing as orange
rods and plates.
Mechanochemistry. Neat grinding (NG) of the co-formers in their respective 1:1 and 2:1 molar ratios
in a mortar and pestle yielded co-crystals, as confirmed by powder X-ray diffraction (see ESI Figs S2-9).
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The only exception was IP-BQ, which only produced the 1:1 form on grinding. Grinding experiments
were performed using 10 mg of benzoquinone with the appropriate equivalent amount of halophenol
(see Table 2 for masses). The two components were added to a mortar and ground for 2-5 minutes
with a pestle. The color of the resulting co-crystal powders for all 1:1 forms, apart from the IP-BQ
cocrystal, was orange-light brown, whereas all 2:1 powders were dark brown-red in color (Figures S16-
S19).
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In order to establish whether conversion to the -phase of co-crystal -1a could be carried out
by extended grinding, selected liquid-assisted grinding experiments were performed. A 100 mg sample
of the -1a co-crystal powder was added to a 15 ml stainless steel milling jar with two stainless steel
balls, using an FTS1000 ball mill from Form-Tech Scientific. The samples of co-crystal were combined
with 25 μL chloroform and ground for 20 minutes at 1800 rpm. No conversion to -1a was observed:
the resulting powder pattern matches that of the neat grinding experiments (Fig. S14).
Instrumentation. Ambient temperature powder X-ray diffraction profiles were collected using a
PANalytical X’Pert Pro Instrument, with CuKα radiation (λ = 1.5418 Å, 40 kV, 30 mA) and Bragg-
Brentano geometry. 2θ scans were performed in the range 4-50° with a 0.016° step size.
Infrared spectroscopy (IR) was performed on a Bruker ALPHA ATR-FTIR.
Single crystal X-ray data were collected on a Bruker D8 Venture diffractometer using the
Apex357 software. The diffractometer is equipped with a microfocus MoKα sealed-tube X-ray source
as well as a Photon II detector. It is fitted with an Oxford Cryostream 800 Series cryostat. Data
reduction and absorption corrections were done using SAINT57and SADABS,57,58 respectively. For the
purposes of this work, the data for the known co-crystals were recollected at 100 K. Structures were
solved and refined using the SHELXS59and SHELXT60,61using XSEED62,63as the interface.
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Acknowledgements
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We acknowledge the National Research Foundation‡ of South Africa, Rhodes University and
Stellenbosch University for funding. We thank D de Villiers for assistance in the development of the
sublimation apparatus.
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‡ This material is based upon work supported financially by the National Research Foundation. Any
opinion, findings and conclusions or recommendations expressed in this material are those of the
author(s) and therefore the NRF does not accept any liability in regard thereto.
The Supporting Information is available free of charge at https://pubs.acs.org. The ESI contains details
on the glassware used for the sublimation experiments, powder X-ray diffraction data, thermal analysis
data, tabulated crystal structure data, HOMO and LUMO orbital energies for the p-halophenol and p-
benzoquinone co-formers calculated using DFT, mechanochemistry and FTIR spectra.
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AUTHOR INFORMATION
Corresponding Author
*v.smith@ru.ac.za
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Author Contributions
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All authors contributed to the writing of the manuscript and approved the final version of the
manuscript.
CCDC deposit codes: 1959377-1959385
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For Table of Contents Use Only.
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Co-crystals: solution, mechanochemistry and sublimation
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Thalia Carstens, Delia A. Haynes and Vincent J. Smith*
Synopsis: Co-crystallization of a series of p-halophenols with benzoquinone using solution
recrystallization, mechanochemistry and sublimation.
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