Angewandte
Chemie
DOI: 10.1002/anie.201301351
Halogen Bonds
Organocatalysis by Neutral Multidentate Halogen-Bond Donors**
Florian Kniep, Stefan H. Jungbauer, Qi Zhang, Sebastian M. Walter, Severin Schindler,
Ingo Schnapperelle, Eberhardt Herdtweck, and Stefan M. Huber*
[
14b]
[14c]
Over the last 15 years, hydrogen-bond donors, such as
thiourea derivatives, have been used as noncovalent organo-
catalysts with ever-increasing sophistication. Yet, despite
the large structural variety of the currently known non-
covalent organocatalysts, virtually all are based on the same
interacting atom: positively polarized hydrogen.
pyridinium,
or 1,2,3-triazolium
backbones) proved to
be active, and stoichiometric amounts of the halogen-bond
donor needed to be employed. As the use of cationic
compounds comes along with several limitations (for exam-
ple, concerning solubility, synthetic accessibility, and the
presence of counteranions), our next goal was to design
neutral halogen-bond donors for use as activators or, ideally,
organocatalysts.
At present, our studies have primarily proof-of-principle
character to demonstrate the feasibility of halogen-bond-
based organocatalysis. In the long term, we envision that
halogen-based organocatalysts and hydrogen-bond donors
will complement each other. Halogen-bond donors might be
especially suitable for Lewis basic substrates featuring heavier
elements (such as sulfur, phosphorous, or the halogens) or for
certain reaction conditions. Furthermore, neutral fluorinated
halogen-bond donors will likely allow the use of very non-
polar or fluorinated solvents in organocatalysis. Finally, the
high directionality of halogen bonds might prove advanta-
geous in future halogen-bond-catalyzed enantioselective
[
1]
Although it has been known for a long time that
compounds featuring electrophilic halogen substituents also
[2]
form adducts with Lewis bases, the corresponding inter-
[
3,4]
action (“halogen bonding”)
1
was mostly ignored until the
[5]
990s. An important difference between these two non-
covalent interactions is the invariably high directionality of
halogen bonds, with RÀXÀLB angles that are close to 1808
[
3]
(
X = Cl,Br,I; LB = Lewis base). Most studies involving
halogen bonds are related to the solid state and to crystal
[6]
engineering, but in recent years an increasing number of
[7]
applications in solution-phase have been published, includ-
[
8]
[9]
ing fundamental studies and reports on anion receptors.
In organocatalysis, the involvement of halogen bonds has
[
10,11]
only been postulated in two cases.
that iodoperfluoroalkanes catalyze the reduction of quinoline
Bolm et al. reported
transformations.
[10a]
[13a]
derivatives.
The participation of halogen bonds in this
In analogy to thiourea organocatalyst 1,
we strove to
reaction was derived from experimental observations. In
a second example, iodine trichloride was reported to catalyze
develop multidentate halogen-based Lewis acids without
further functional groups to study the isolated effect of
halogen bonding. The 2,6-diiodo-3,4,5-trifluorophenyl group
(Scheme 1) was chosen as building block for several reasons,
[
10b]
the ring-opening polymerization of l-lactide.
The elucida-
[12]
tion of the exact mode of action of this highly reactive
interhalogen compound is not trivial, though, and in both
reported cases the analysis is further complicated by the
[7b]
possible presence of traces of acid.
One particular application of hydrogen-bonding organo-
catalysts is based on the coordination to anions and/or the
abstraction of the latter from organic substrates (“anion
[
13]
binding mechanism”).
Recently, we could show that
Scheme 1. Thiourea organocatalyst 1, and the design principle for
neutral multidentate halogen-bond donors (2).
halogen-bond donors may also serve as activators in
[
14]
a halide-abstraction benchmark reaction. To date, however,
[14a]
only dicationic compounds (based on either imidazolium,
namely: a) the electron-withdrawing fluorine substituents;
b) the fact that high rigidity can be achieved by coupling to
aryl moieties; and c) the fact that the formation of atrop-
isomers can be avoided owing to the symmetry of this group.
Orientating DFT studies to identify suitable backbones
suggested that p- or m-substituted benzene should constitute
ideal core structures (see the Supporting Information). Few
[
+]
[+]
[
*] F. Kniep, S. H. Jungbauer, Q. Zhang, S. M. Walter, S. Schindler,
I. Schnapperelle, Dr. E. Herdtweck, Dr. S. M. Huber
Department Chemie,Technische Universitꢀt Mꢁnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
E-mail: stefan.m.huber@tum.de
+
[
] These authors contributed equally to this work.
[
**] Our research is funded by the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft, the Leonhart Lorenz Founda-
tion, and the Dr. Otto Rçhm Gedꢀchtnisstiftung. We thank Florian
Mayr, Tobias Kapp, and Olaf Ackermann for experimental contri-
butions. We also thank Prof. Dr. Thorsten Bach for continuing
support.
neutral multidentate halogen-bond donors are known, and
[8f,9a,b]
those either lack the desired rigidity
or do not point their
[15]
electrophilic halogen substituents towards a single center.
The presence of several iodine substituents in compounds
of type 2 severely restricts the use of cross-coupling strategies
for their synthesis. Our first successful synthetic route
(Scheme 2) consisted of a twofold nucleophilic aromatic
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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