Constructing, deconstructing, and reconstructing ternary supermolecules

Article abstract of DOI:10.1039/b707518a

A hypothesis-driven protocol comprising precise and predictable molecular recognition events based upon an electrostatic view of competing hydrogen-bond interactions is proposed and subsequently employed in the construction of ternary co-crystals. The Royal Society of Chemistry.

Full text of DOI:10.1039/b707518a

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Constructing, deconstructing, and reconstructing ternary
supermolecules{{
Christer B. Aaker o¨ y,* John Desper and Michelle M. Smith
Received (in Cambridge, UK) 18th May 2007, Accepted 25th July 2007
First published as an Advance Article on the web 10th August 2007
DOI: 10.1039/b707518a
A hypothesis-driven protocol comprising precise and predict-
able molecular recognition events based upon an electrostatic
view of competing hydrogen-bond interactions is proposed
and subsequently employed in the construction of ternary
co-crystals.
1
The design, construction, properties and even the definition
2
3
4
of molecular co-crystals have received considerable attention
recently. This intense interest can be explained in part because
co-crystallization reactions offer unique opportunities for examin-
ing the balance between and structural influence of intermolecular
interactions. However, co-crystals may also be of considerable
practical and economic importance, notably to the pharmaceutical
Scheme 1 Protocol for deconstructing and reconstructing ternary co-
crystals. D and D = hydrogen-bond donors, A and A = hydrogen-
bond acceptors.
1
2
1
2
Recently we demonstrated how ditopic hydrogen-bond accep-
tors based on pyridyl/benzimidazole can act as a hub for the
5
industry. Despite a wealth of publications detailing new co-
6
crystals, very few of them describe examples composed of three or
assembly of ternary co-crystals in combination with two carboxylic
8
acids of different strengths. The stronger acid (based upon pK
a
-
more different molecular building blocks assembled using precise
7
and well-defined supramolecular synthons; bringing three differ-
values) binds to the best hydrogen-bond acceptor (the more basic
N-heterocycle) whereas the weaker acid binds to the second-best
ent molecular species into one crystalline lattice without making or
breaking covalent bonds, is still exceedingly difficult.
a
acceptor site. The use of pK values for identifying the better
9
hydrogen-bond donor can work within a family of compounds,
but such data offers no reliable information when comparing
hydrogen-bond donor/acceptor strength for different functional
Herein, we provide a hypothesis-driven protocol for the
construction of ternary supermolecules and co-crystals where
stoichiometry and primary intermolecular interactions can be
readily rationalized. Our approach is based upon three comple-
mentary steps:
10
groups. Instead, Hunter has shown how calculated molecular
electrostatic potential (MEP) surfaces can be employed for
assigning (and ranking) the relative hydrogen-bond donor/
acceptor strengths across a wide range of chemical functional-
I. Allow a series of ditopic molecules equipped with two
different hydrogen-bond acceptors to react with a molecule
containing two different hydrogen-bond donor moieties. Use
structural data for the resulting binary 1 : 1 co-crystals to establish
intermolecular pattern preferences.
11
ities. The calculations can be performed at a relatively low level
of theory (AM1), which makes this a versatile and readily
accessible tool.
In order to test our hypothesis we employed four asymmetric
ditopic hydrogen-bond acceptors, (1–4), Scheme 2 and two
asymmetric ditopic hydrogen-bond donors, 5–6, Scheme 3.
The maxima/minima on the AM1-based MEPs for 1–8 are
II. Once complementary hydrogen-bond interactions can be
ranked according to frequency of occurrence, use covalent
synthesis to deconstruct one of the ditopic compounds into
mono-functional components (I).
12
listed in Table 1.
III. Combine a ditopic ligand (with two hydrogen-bond
acceptors) and two different hydrogen-bond donors in the
deliberate synthesis of a specific ternary co-crystal (II), Scheme 1.
This approach requires a library of ditopic supramolecular
reagents that contain either two different hydrogen-bond donors
or two different hydrogen-bond acceptors that can be ranked
according to relative hydrogen-bonding capability.
We now begin to construct co-crystals with the assumption that
the hydrogen bonds in this system are primarily electrostatic in
nature. Consequently, by applying the best donor/best acceptor,
second-best donor/second-best acceptor rationale, in the context of
the calculated charges in these molecules, we can postulate which
molecular recognition events will most likely appear in the
resulting crystal structures.
Department of Chemistry, Kansas State University, Manhattan, KS,
66506. E-mail: aakeroy@ksu.edu
{
CCDC 647757–647758 and 652592–652593. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b707518a
Electronic supplementary information (ESI) available: Synthesis of
supramolecular reagents. See DOI: 10.1039/b707518a
{
Scheme 2
3
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Scheme 3
2
1
)
Fig. 2 In 26, the best hydrogen-bond donor (phenol), binds to the best
acceptor, while the second-best donor (carboxylic acid) interacts with the
second-best acceptor.
Table 1 Calculated MEPs for 1–8 (in kJ mol
Molecule
MEP for A
1
MEP for A
2
1
2
3
4
2299
2311
2301
2299
2274
2271
2255
2269
moiety. We therefore needed to find out how a single oxime
moiety would behave (in the absence of a competing donor) when
faced with a ditopic molecule such as 1–4.
Molecule
MEP for D
1
MEP for D
2
The co-crystallization of 4-bromocyanophenyloxime, 9, and 3
produced suitable crystals, 39, Fig. 3, where the oxime moiety
5
+190
+197
+171
+129
+152
+136
—
…
interacts with the benzimidazole moiety (O47 N13 2.6100(15) A).
˚
6
Phenylcyanooxime, 7
Pentamethylbenzoic acid, 8
16
We now have support, from three different crystal structures,
—
that a binding preference and hierarchy of intermolecular
interactions based upon simple MEPs can be employed as the
basis for a versatile supramolecular synthetic strategy. In order to
prepare a ternary co-crystal, a ditopic hydrogen-bond donor was
deconstructed into separate fragments, that were subsequently
allowed to react, in a 1 : 1 : 1 ratio, with the ditopic hydrogen-bond
acceptor 4. Phenylcyanooxime, 7, ranks as a better hydrogen-bond
First, we examined the outcome of co-crystallization reactions
between 1–4 and 6–7. The combination of 1 (with benzimidazole
and pyridine) and 5 (comprising cyanoxime and a carboxylic acid)
produced crystals, 15, suitable for single-crystal X-ray diffraction.
13
Both cyanoximes and carboxylic acids are known to be effective
1
4
17
co-crystallizing agents, but the MEPs indicate that the oxime
moiety is the best hydrogen-bond donor, which should make it
bind preferentially to the more basic benzimidazole site on 1.
The primary intermolecular interactions in the structure of the
binary 1 : 1 co-crystal 15 are shown in Fig. 1.
donor, than pentamethylbenzoic acid, 8, and the structural
outcome is shown in Fig. 4.
The construction of the primary supermolecule in 478 is
…
achieved via two O–H N hydrogen bonds. The cyanooxime
…
binds to the benzimidazole moiety (O37 N13, 2.6396(19) A), and
˚
…
The two primary recognition events take place as expected,
the carboxylic acid interacts with the pyridine site (O51 N21,
(based upon an electrostatic argument), and comprise two
…
different O–H N hydrogen bonds; O48 N13, 2.603(3) A
…
˚
… … …
˚
(
oxime benzimidazole), O41 N31, 2.612(3) A (acid pyridine).
The second suitable crystalline sample came from the reaction
between 2 and 6. The relative strengths of the two hydrogen-bond
donors/hydrogen-bond acceptors on 6 are indicated by the MEP’s
in Table 1. This ranking is also consistent with established pKHB
10,15
values.
The primary recognition events take place as expected, Fig. 2,
…
and comprise two hydrogen bonds; O44 (phenol) N13 (imida-
˚
…
˚
˚
zole) 2.659(3) A and O41 (acid) N21 (pyridine) A 2.693(2) A.
The two structures obtained so far do support our initial
hypothesis, but it is conceivable that the carboxylic acid is, in fact,
determining the connectivity in both 15 and 26 by preferentially
binding (and outcompeting the other donors) to the pyridine
Fig. 3 The only hydrogen-bond donor in 39 binds to the acceptor with
the largest MEP, the imidazole moiety, thus confirming the best-donor/
best-acceptor premise.
Fig. 1 In 15, the best hydrogen-bond donor (oxime), binds to the best
acceptor, while the second-best donor (carboxylic acid) interacts with the
second-best acceptor.
Fig. 4 Ternary supermolecule in the crystal structure of 478 shows that
the best donor (oxime), binds to the best acceptor, and the second-best
donor (carboxylic acid), binding to the second-best acceptor.
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938 | Chem. Commun., 2007, 3936–3938
This journal is ß The Royal Society of Chemistry 2007