Structural competition between hydrogen bonds and halogen bonds

Article abstract of DOI:10.1021/ja073201c

The molecules presented here provide a test-bed for competitive supramolecular chemistry, and on the basis of five crystal structures a ranking of the relative structural importance and influence of competing weak/strong hydrogen bonds and weak/strong hal

Full text of DOI:10.1021/ja073201c

Published on Web 10/23/2007
Structural Competition between Hydrogen Bonds and Halogen Bonds
Christer B. Aakero¨y,*,† Meg Fasulo,† Nate Schultheiss,† John Desper,† and Curtis Moore‡
Department of Chemistry, Kansas State UniVersity, Manhattan, Kansas 66506, and Department of Chemistry,
Wichita State UniVersity, 1845 Fairmount, Wichita, Kansas 67260
Received May 6, 2007; E-mail: aakeroy@ksu.edu
One of the main difficulties with directed-assembly of specific
multicomponent supermolecules or extended architectures arises
because such synthetic operations are typically limited to one-pot
processes, as the desired products are held together by noncovalent
and readily reversible interactions.1 One way to overcome such
restrictions may be to identify hierarchies of intermolecular
interactions and then to develop supramolecular synthetic strategies
that utilize synthons2 that can operate side-by-side without interfer-
ing with each other. This type of approach has been employed
successfully in the construction of ternary cocrystals, where
Figure 1. Electrostatic charges for the hydrogen-bond donors/acceptor sites
in 1-4 based on AM1 calculated MEP’s.
hydrogen bonds of different strengths are responsible for organizing
three molecular building blocks into supermolecules in a predictable
manner.3
However, a strategy that exclusively relies on hydrogen bonds
could soon run into problems as it would become increasingly
difficult to avoid crossover reactions between multiple hydrogen-
bond based synthons that compete with each other in one reaction
mixture. Consequently, it may be useful to incorporate halogen
bonds, intermolecular interactions where halogen atoms act as
electrophiles, into this approach. Halogen bonds have characteristics
that parallel those of hydrogen bonds in terms of strength and
directionality,4 and N‚‚‚I halogen bonds have been employed
frequently in supramolecular chemistry.5 The question is, can we
develop effective supramolecular synthetic strategies around a
hierarchy of synthons that comprise both hydrogen and halogen
bonds?
Figure 2. Thermal-ellipsoids plot (50% probability level) of 3 and the
oxime‚‚‚oxime dimer.
Herein, we address this question through a series of cocrystal-
lization reactions between a ditopic structural probe molecule, 1,
containing two sites (pyridyl and benzimidazole) that can act as
either hydrogen-bond or halogen-bond acceptors. The counterpart
will be a molecule containing a weak and a strong hydrogen-bond
donor as well as one potential halogen-bond donor (Figure 1).
With two acceptors and three donors, every cocrystal is likely
to end up with one donor without a partner allowing the different
synthons to be ranked according to relative structural influence.
Molecular electrostatic potential (MEP) calculations6 were carried
out on 1-4 to identify the best hydrogen-bond donor/acceptor and
second-best donor/acceptor sites; this ranking is based on the
assumption that electrostatic interactions dominate conventional
hydrogen bonds.7 The values indicate that the benzimidazole moiety
is a better hydrogen-bond acceptor than the pyridine functionality,8
and the -OH (oxime) site is a better hydrogen-bond donor than
the imine -CH moiety. In addition to the examination of three
cocrystals, we also obtained crystal structures for 3 and 4, to
compare the structural balance between hydrogen bonds and halogen
bonds (-Br vs -I).
Figure 3. 2-D sheet generated through a combination of self-complemen-
tary hydrogen bonds and I‚‚‚I interactions.
producing a common oxime‚‚‚oxime dimer. There are, however,
no short Br‚‚‚Br contacts in this structure (Figure 2).
The crystal structure of 4 also contains oxime‚‚‚oxime dimers
formed through symmetry-related O-H‚‚‚N (O‚‚‚N, 2.872(4) Å)
hydrogen bonds. The dimers are organized into a 2-D sheet through
I‚‚‚I bonds, 3.944 Å, (Figure 3). The two C-I‚‚‚I angles, 108° and
143°, respectively, indicate that these contacts are due to specific
(and attractive) polarization induced type II interactions.9
To establish a relative ranking of competing supramolecular
synthons, we subsequently prepared three cocrystals 12-14, by
allowing 1 to react in a 1:1 stoichiometry with 2-4, respectively.
In 12 (the 1:1 cocrystal of 1 and 2), the best hydrogen-bond
donor, the oxime moiety, binds to the benzimidazole site, O-
H‚‚‚N (O‚‚‚N, 2.671(3) Å), which is the best hydrogen-bond
acceptor (Figure 4a). Since -F is a very poor halogen-bond donor,
the remaining N-heterocycle instead engages with the imine proton
C-H‚‚‚N (C‚‚‚N, 3.43 Å), leading to an infinite 1-D tape-like motif.
The crystal structure of 3 is dominated by a pair of self-
complementary O-H‚‚‚N hydrogen bonds (O‚‚‚N, 2.855(2) Å)
† Kansas State University.
‡ Wichita State University.
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10.1021/ja073201c CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
14, the oxime -OH moiety preferentially engages in an O-H‚‚‚N
hydrogen bond with the former, which is in line with the MEP-
guided hierarchy. The remaining pyridyl site could have become a
participant in either a halogen bond or a hydrogen bond involving
an acidic C-H group. In this race for the py group, only the iodo
substituent was strong enough to compete successfully with the
C-H imine. This structural advantage of N‚‚‚I bonds over N‚‚‚Br
bonds is also reflected by the fact that the CSD11 only contains 13
molecular cocrystals assembled through N‚‚‚Br interactions, whereas
there are more than 50 cocrystals constructed using N‚‚‚I bonds.
This structural study, albeit performed on a relatively small
number of compounds, indicates that a good hydrogen-bond donor
is likely to be very competitive for a N-heterocyclic moiety, even
in the presence of a fluoro-activated organoiodine. The latter group
is, however, capable of displacing a less conventional hydrogen-
bond donor such as the C-H imine moiety. Furthermore, since
C-Br is a significantly weaker Lewis acid than the C-I group, it
does not form a halogen bond that can compete with the C-H‚‚‚N
hydrogen bonds in 12 and 13. The structures presented herein are
primarily governed by hydrogen and halogen bonds but the final
crystal structure is of course the result of a balance of numerous
weak and rather unpredictable interactions (fluorine segregation,12
however, does not seem to play a discernible role in this series of
compounds).
Figure 4. (a) The 1:1 cocrystal of 12; (b) extended architecture through
multiple hydrogen bonds.
Figure 5. (a) The 1:1 cocrystal of 13; (b) 1-D chain produced through
multiple hydrogen bonds.
Systematic cocrystallization reactions that probe the balance
between, and structural outcome of, a mixture of hydrogen bonds/
halogen bonds will undoubtedly assist in developing versatile
strategies for the future assembly of discrete supermolecules and
heteromeric molecular architectures.
Acknowledgment. We are grateful for the financial support
from NSF (Grant CHE-0316479) and the Terry C. Johnson Center
for Basic Cancer Research and for a DURIP-ARO instrumentation
grant.
Supporting Information Available: Detailed experimental pro-
cedures for compounds 1-4, along with crystallographic data and CIF
files for 3, 4, 12, 13, and 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 6. (a) The 1:1 cocrystal of 14; (b) tetrameric supermolecule
constructed through hydrogen bonds and halogen bonds.
References
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In 13 (the 1:1 cocrystal of 1 and 3) the oxime -OH proton forms
a hydrogen bond to the benzimidazole site, (O‚‚‚N, 2.675(3) Å),
as was the case in 12, which leaves the pyridine moiety free to
pick up the imine proton, a significantly weaker hydrogen-bond
donor, (C‚‚‚N, 3.42 Å), resulting in a 1-D extended architecture,
(Figure 5a and b).
Although N‚‚‚Br halogen bonds are known to be of sufficient
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In 14 (a 1:1 cocrystal of 1 and 4) a hydrogen bond is again
formed between the -OH oxime and benzimidazole moiety, (O‚‚‚N,
2.706(6) Å). However, this time the iodo-substituent in 4 (“acti-
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group resulting in a four-component supermolecule (Figure 6).
The benzimidazole moiety carries a larger negative MEP than
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(8) This ranking is in agreement with a hydrogen-bond scale based upon ∆G
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