Controlling molecular tautomerism through supramolecular selectivity

Article abstract of DOI:10.1039/c3cc43935f

We have isolated the stable as well as the metastable tautomers of 1-deazapurine in the solid state by exploiting principles of supramolecular selectivity in the context of cocrystal design.

Full text of DOI:10.1039/c3cc43935f

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Controlling molecular tautomerism through
supramolecular selectivity†
Cite this: DOI: 10.1039/c3cc43935f
Kanishka Epa,a Christer B. Aakeroy,a John Desper,a Sundeep Rayat,b
¨
Received 25th May 2013,
Accepted 4th July 2013
Kusum Lata Chandraa and Aurora J. Cruz-Cabeza*c
DOI: 10.1039/c3cc43935f
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We have isolated the stable as well as the metastable tautomers of observed tautomeric form of a compound. Whilst relatively
1-deazapurine in the solid state by exploiting principles of supra- little control can be gained over the way in which a compound
molecular selectivity in the context of cocrystal design.
chooses to crystallize by itself, the introduction of additional
components into the lattice opens up a range of new possibi-
All molecules capable of tautomerism can present multiple lities. The aim of this contribution is to demonstrate how it is
chemical expressions towards their surroundings. Consequently, possible to command molecular tautomerism by exploiting
properties such as acidity, hydrophobicity or polarity can vary concepts of supramolecular selectivity in the context of cocrystal
considerably between different tautomers of the same com- design.11,12 To demonstrate the fundamental principles of
pound.1 Since hydrogen atoms are difficult to locate using X-ray our approach, we chose imidazo[4,5-b]pyridine, 1-deazapurine
diffraction techniques, prototropic tautomers2,3 have often (1-DAP), as a model compound. 1-DAP can exhibit two different
been overlooked or even miss-assigned. The problem of tautomers: 3H and 1H (Fig. 1). Tautomer 3H is always more
‘‘tautomeric blindness’’ has adversely affected many hierarchies stable than the 1H tautomer, even in markedly different polar-
of structural sciences from small molecule crystal structures to izable environments (Fig. 1 and Table S1, ESI†).
biological macromolecules, including DNA.4
In order to sample the likely aggregation modes of both
Whilst many compounds may tautomerize in solution, they tautomers of 1-DAP, we used computational methods (Crystal-
are almost invariably frozen into a particular tautomeric form Predictor)13 to generate Z0 = 1 crystal structures of both tautomers.
once they aggregate in a solid. In fact, 99.5% of tautomeric Computer generated crystal structures containing the 3H tautomer
molecules only exhibit one tautomeric form in the crystalline revealed a preference of 3H-1-DAP to form hydrogen bond
state,5 and this usually corresponds to the most stable tautomer dimers (Fig. 2, left). Computer generated crystal structures
(except when the tautomeric energy differences are small, containing the 1H tautomer revealed a preference of 1H-1-DAP
o5 kJ molꢀ1).6 In those rare cases where higher-energy tauto- to form catemeric motifs (Fig. 2, right). In these aggregation
mers are observed,7 tautomeric energy differences almost never modes, both tautomers end up with one unused basic nitrogen
exceed the interaction energy of a strong hydrogen bond.5 It atom (the imidazole nitrogen for the 3H tautomer and the
appears that the less stable a tautomer is, the more challenging pyridine nitrogen for the 1H tautomer).
its isolation becomes within a crystalline phase. For example, it
In order to extract a desirable tautomer from solution and
has taken 137 years to discover and characterize the most stable into the solid state, regardless of its relative stability, we opted
polymorph of barbituric acid, a polymorph containing the for a strategy based on molecular-recognition driven cocrystal-
considerably higher-energy enolic tautomer.8
lization whereby the face of a specific tautomer is selectively
A change in polymorphic structure5,9 or a change in lattice
components10 may, in some cases, induce a change in the
a Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
b Department of Chemistry, Ball State University, Cooper Physical Science Building,
Muncie, IN 47306, USA
c Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park
904, 1098 XH Amsterdam, The Netherlands. E-mail: aurorajosecruz@gmail.com
† Electronic supplementary information (ESI) available: Experimental and com-
putational details and crystallographic and spectroscopic data. CCDC 937212–
937217. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc43935f
Fig. 1 3H and 1H tautomers of 1-DAP. Relative tautomeric energies were
calculated at the CCD/aug-cc-pVTZ level of theory in the gas-phase and using
a Polarizable Continuum Model (ESI†).
c
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(U1–U14) was used as a source of selective cocrystal formers for
the 1H tautomer (Fig. 3, right).
1-DAP and the coformers were either synthesized or pur-
chased as detailed in the ESI.† Cocrystal formation was
attempted by grinding 1 : 1 solid mixtures of 1-DAP and the
coformer (I/U) in the presence of a few drops of acetone. New
forms were identified using PXRD and FTIR, and single crystals
were obtained via slow evaporation from acetone solutions.
Eight new solid forms were produced by grinding, six of which
were characterized using single crystal XRD (1-DAP cocrystals
with I1, I2, U1, U3, U4 and U13).
All cocrystals obtained in this study contained the desired
Fig. 2 Predicted aggregation modes of 1-DAP in the 3H and 1H tautomers and tautomeric forms as well as the intended supramolecular
supramolecular synthons proposed for their selective isolation.
synthons. In the two cocrystals of 1-DAP with the coformers
I1 and I2, tautomer 3H is present (Fig. 4, left). As intended, the
3H dimer (held together by two N–Hꢁ ꢁ ꢁN hydrogen bonds) is
matched with a complementary molecule. First, to selectively
intact, leaving the halogen-bond donor to engage the peripheral
isolate the more stable 3H tautomer, we decided to cocrystallize
nitrogen atom, which results in discrete tetrameric super-
1-DAP with a molecule capable of interacting strongly with the
molecules in both structures (the second halogen atom in each
available imidazole nitrogen atom in the 3H tautomer without
I coformer does not display any significant intermolecular
perturbing the hydrogen-bond dimer. We chose a halogen-
interactions). In the four cocrystals of 1-DAP with the urea
bond donor since such a molecule should interact favourably
coformers U1, U3, U4 and U13, the desired meta-stable tautomer
at the 3H imidazole nitrogen with a lower probability of
1H is indeed obtained (Fig. 4, right). As intended, the urea
disturbing the 3H dimer or the 1H catemeric motif (Fig. 2).
coformer inserts itself in the original catemeric motif through
Consequently, we employed two well-established halogen-bond
two hydrogen bonds at one end and one hydrogen bond at the
donors (I1 & I2) as selective cocrystal formers for the 3H
opposite end of the molecule (Fig. 4, right) and in each case the
tautomer (Fig. 3, left). Second, to selectively isolate the
primary motif is an infinite chain of alternating urea-1H
metastable 1H tautomer, we needed a cocrystallizing agent
building blocks. The success rate for crystallizing the less-
capable of forming two coplanar hydrogen bonds (both as
stable 1H tautomeric form was 43% (6/14) as indicated using
donors) separated by a distance of B2.4 Å (the distance
infrared spectroscopy on all solid products (ESI†).
between the imidazole and the pyridine basic nitrogen atoms
Energies of the main dimers in these cocrystals were calcu-
in the 1H tautomer) with an accessible hydrogen-bond acceptor
lated and are summarized in Table 1 for two representative
at the opposite end of the molecule (Fig. 2, right). Such a
cocrystals of each type. Dimer energies were calculated by fully
partner should selectively interact with the 1H tautomer by
geometry optimizing the experimental crystal structure of the
inserting itself in the catemeric motif, while leaving the 3H
cocrystal using VASP14 (PBE15 DFT functional with Grimme’s16
tautomer unperturbed. A search of the Cambridge Structural
van der Waals corrections, PBE-d) and then performing a single
Database for such molecular topologies resulted in several
point energy calculation of the isolated dimer of interest and a
possible candidates including urea derivatives (ESI†). Since
full geometry optimization of the isolated monomers using the
metastable tautomers are usually more difficult to crystallize
same model. The energy difference between the dimer and the
than stable tautomers, an extensive library of diphenyl ureas
monomers corresponds to the reported dimer energy in
Table 1. In the cocrystals containing the 3H tautomer, 3H is
involved in two main dimer interactions: (i) with another 3H
molecule of ꢀ97 kJ molꢀ1 (involving two hydrogen bonds) and
(ii) with a I molecule of ꢀ37 kJ molꢀ1 (involving a strong
halogen bond). In the cocrystals containing the 1H tautomer,
1H is involved in two main interactions with U of Bꢀ80 kJ molꢀ1
(involving two hydrogen bonds) and Bꢀ48 kJ molꢀ1 (involving
an additional hydrogen bond). Each 1-DAP coformer inter-
action present in these cocrystals is far more stabilizing than
the tautomeric energy of the 1H tautomer itself (Fig. 1), hence,
it is not surprising that supramolecular interactions can pro-
vide an effective way of controlling tautomeric forms. Overall,
the interactions involving the 3H and the 1H tautomers of
1-DAP are very similar in both types of cocrystals. However,
whilst in the 3H:I cocrystals the motifs are isolated (a tetramer
unit), in the 1H:U cocrystals they extend infinitely as part of a
catemer motif.
Fig. 3 Cocrystal formers used for the selective crystallization of the stable 3H
tautomer (left) and the metastable 1H tautomer (right) of 1-DAP.
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Fig. 4 Motifs found in the 1:1 cocrystals of (a) 1-DAP as the stable 3H tautomer with I2 and I1 and (b) 1-DAP as the metastable 1H tautomer with U3, U13, U4 and U1.
Table 1 Dimer energies (kJ molꢀ1) between one molecule of 1-DAP and its two
contribution may prove very useful for the design of new
materials containing rare tautomeric forms, which are likely
closest neighbours in four relevant cocrystals
to exhibit very different physical properties. This should be of
Dimer interacting through
interest to many research areas dealing with the solid-state
Two hydrogen bonds
(3H–3H)
One halogen bond
(3H–I)
properties of high-value active ingredients and materials.
AJCC acknowledges the Netherlands Organization for Scientific
Research for a VENI grant.
Cocrystal
3H:I1
3H:I2
ꢀ96.5
ꢀ98.1
ꢀ36.5
ꢀ37.9
Two hydrogen bonds
(1H–U)
One hydrogen bond
(1H–U)
Notes and references
‡ This structure was later found to correspond to the crystal structure
observed experimentally.20
1H:U1
1H:U13
ꢀ74.0
ꢀ86.1
ꢀ48.3
ꢀ47.3
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´
´
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