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ꢀ
1
Table 2, a charge of ꢀ275 kJ mol or higher resulted in salts
whereas charges between ꢀ260 and ꢀ230 resulted in a gradually
decreasing ability to form co-crystals. Finally, compound G, with
a charge on the pyridyl nitrogen atom equivalent to ꢀ220 kJ
2
ꢀ1
mol , only produced one acid–base reaction. It is clear that in
attempted reactions between this compound and acids 1–15, the
acid/acid dimers prevailed since the base failed to offer enough
stabilizing incentive for a heteromeric assembly.
Our systematic investigation also makes it clear that co-crystal
formation in this system is primarily driven by the charge on the
py-N (ligand) and not by the strength of the carboxylic acid. We
did analyze the results in the context of charges of the carboxylic
acids (the charge on the acidic proton), however, much better
trends/correlations were found between the charges on the
heterocyclic nitrogen atom acids and the intermolecular interac-
tions/results. For example, a stronger acid, 4-nitrobenzoic acid 5,
produced no reaction with 2-acetamido-5-bromopyridine,
whereas a weaker acid, 3-hydroxybenzoic acid 3, gave a co-crystal.
4
5
6
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Our experimental results successfully highlight the relationship
between the electrostatic charge on the N-heterocyclic base and
the ability of the compound to form intermolecular hydrogen
bonds in the solid state. By adding appropriate substituents via
conventional covalent synthesis, we have been able to dial-in the
charge on the primary hydrogen-bond acceptor and this leads to
a predictable change in supramolecular yield of the reaction. Once
the base exceeds a specific value, proton transfer (salt formation) is
inevitable; 30 out of 30 attempted reactions. Conversely, if the
charge on the hydrogen-bond acceptor is too low, co-crystal
formation becomes very unlikely (1/15 reactions) and homomeric
assemblies dominate over heteromeric interactions.
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Despite the fact that numerous intermolecular forces are
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primary hydrogen-bonded synthons can offer considerable
insight into the way in which molecules can be assembled into
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1
1
1
1
1
Acknowledgements
1
1
1
7 C. Li, L. S. Rittmann, A. S. Tsiftsoglou, K. K. Bhargava and
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We are grateful for the financial support from the Johnson
Center for Basic Cancer Research and Boehringer Ingelheim
Pharmaceuticals, Inc.
9 Charge calculations for the structures A–G were performed using
Spartan ’04 (Wavefunction, Inc., Irvine, CA). All seven molecules
were optimized using AM1, with the maxima and minima in the
Notes and references
ꢀ
1
electrostatic potential surface (0.002 e au isosurface) determined
using a positive point charge in the vacuum as a probe.
20 H. G. Brittain, Cryst. Growth Des., 2009, 9, 2492.
1
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This journal is ª The Royal Society of Chemistry 2010
CrystEngComm, 2010, 12, 4231–4239 | 4239