A Bidentate Iodine(III)-Based Halogen-Bond Donor as a Powerful Organocatalyst**

Article abstract of DOI:10.1002/anie.202013172

In contrast to iodine(I)-based halogen bond donors, iodine(III)-derived ones have only been used as Lewis acidic organocatalysts in a handful of examples, and in all cases they acted in a monodentate fashion. Herein, we report the first application of a bidentate bis(iodolium) salt as organocatalyst in a Michael and a nitro-Michael addition reaction as well as in a Diels–Alder reaction that had not been activated by noncovalent organocatalysts before. In all cases, the performance of this bidentate XB donor distinctly surpassed the one of arguably the currently strongest iodine(I)-based organocatalyst. Bidentate coordination to the substrate was corroborated by a structural analysis and by DFT calculations of the transition states. Overall, the catalytic activity of the bis(iodolium) system approaches that of strong Lewis acids like BF₃.

Full text of DOI:10.1002/anie.202013172

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Accepted Article
Title: A bidentate iodine(III)-based halogen-bond donor as a powerful
organocatalyst
Authors: Flemming Heinen, Dominik Reinhard, Elric Engelage, and
Stefan Matthias Huber
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A bidentate iodine(III)-based halogen-bond donor as a powerful
organocatalyst
[a]
[a]
[a]
[a]
Flemming Heinen, Dominik Reinhard, Elric Engelage, and Stefan M. Huber*
In memoriam François Diederich
Abstract: In contrast to iodine(I)-based halogen bond donors,
iodine(III)-derived ones have only been used as Lewis acidic
organocatalysts in a handful of examples, and in all cases they acted
in a monodentate fashion. Herein, we report the first application of a
bidentate bis(iodolium) salt as organocatalyst in a Michael and a nitro-
Michael addition reaction as well as in a Diels-Alder reaction that had
not been activated by noncovalent organocatalysts before. In all
cases, the performance of this bidentate XB donor distinctly
surpassed the one of arguably the currently strongest iodine(I)-based
organocatalyst. Bidentate coordination to the substrate was
corroborated by a structural analysis and by DFT calculations of the
transition states. Overall, the catalytic activity of the bis(iodolium)
techniques.[17] After Han and Liu had reported the use of
diaryliodonium salts as catalysts in a Mannich reaction,[18] our
group demonstrated that the catalytic activity of cyclic iodolium
salts in
a
halide abstraction reaction and
a
Diels-Alder
[19]
cycloaddition is indeed very likely due to XB.
Further halide
abstraction reactions were subsequently published by
Aoshima,[ Nachtsheim
20]
[21]
and our group (activating a metal-
halogen bond[21]).
In several of these reactions,[19,22] the iodolium catalysts showed
comparable activity to “classical” bidentate iodine(I) XB donors.
This strong performance is particularly noteworthy since the
iodine(III) derivatives act as monodentate XB donors (Figure 1
middle), even though they in principle feature two electrophilic
axes,[15,16,23,24] All chemical intuition suggest, however, that
bidentate iodolium variants should be markedly more Lewis acidic
and should likely surpass the currently best catalysts in activity
3
system approaches that of strong Lewis acids like BF .
Halogen bonding (XB) describes the non-covalent interaction
between an electrophilic halogen substituent (called “XB donor”)
and a Lewis base (called “XB acceptor”).[1] It has found broad
(
Figure 1 right). Herein, we present the first application of such a
bidentate iodine(III)-based XB donor as organocatalyst.
application[2] in numerous fields like crystal engineering[3],
molecular and anion recognition[
1c, 4]
as well as peptide
chemistry.[ In the last decade, halogen bonding has also been
established in organocatalysis and has been applied in various
organic reactions.[6] So far, virtually all employed halogen bond
donors were based on iodine(I) derivatives, with backbones
ranging from polyfluorinated aromatics to imidazolium or
5]
Figure 1. Schematic representation of: bidentate iodine(I)-based XB (left),
[7]
triazolium derivatives. As expected, cationic XB donors are
more potent catalysts than neutral ones,[8] and bidentate variants
often severely outperform their monodentate analogs. Thus, the
most potent currently available XB catalysts – next to elemental
iodine[9] – typically rely on two cationic iodine(I)-based XB-
donating moieties (e.g. iodobenzimidazolium groups;[7d] see
Figure 1 left).
monodentate iodine(III)-based XB (middle), and bidentate iodine(III)-based XB
(
right).
As suitable core structure, thiophene-linked bis(iodolium) triflate 1
(
Scheme 1) was selected, which had previously been published
[25]
by Yoshikai.
It features a very rigid binding pocket, and is
topologically related to a dithienothiophene-derived chalcogen
bonding organocatalysts introduced by Matile.[26]
Single crystals of compound 1 were obtained by slow evaporation
Iodine(III)-derived compounds, on the other hand, are very
versatile reagents in various organic transformations,[10]
[11]
especially for oxidations of functional groups and for transition-
metal-catalyzed[12] or direct arylations.[13] Diaryliodonium salts
typically feature a T-shaped structure around the central iodine
atom in which the anion is coordinated by “secondary
bonding”.[11a,14] This interaction can be described as XB,[15] and
the corresponding Lewis acidity of iodine(III) derivatives is of
growing interest in recent years, e.g. in theoretical studies.[16] In
pioneering experimental work, Legault et al. quantified the Lewis
acidity of several iodonium salts using various titration
of acetonitrile (Figure 2).
[
a]
F. Heinen, D. Reinhard, Dr. E. Engelage, Prof. Dr. Stefan M. Huber
Fakultät für Chemie und Biochemie
Figure 2. Excerpt of the X-ray structural analysis of XB donor 1. The triflate
Ruhr-Universität Bochum
Universitätsstraße 150, 44801 Bochum, Germany
E-mail: stefan.m.huber@rub.de
anions are disordered. Ellipsoids at 50% probability.
The structure clearly shows bidentate XB between the iodine
centers and one oxygen atom of a counterion (which lies in the
Supporting information for this article is given via a link at the end of
the document.
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plane formed by the I-C-C-I unit). Typical for XB, both I•••O
distances (2.69 - 2.73 Å) are markedly shorter than the sum of the
van-der-Waals radii (3.50 Å)[27] and the corresponding C-I•••O
angles (159 – 160°) are almost linear. The remaining electrophilic
axes on the iodines are also coordinated by triflates, with one
strongly bound anion (Figure 2, left side) and two moderately
bound ones (Figure 3, right side).[28]
did not result in any product formation even when 20 mol-% of
catalyst were used. This confirms that the enhanced activity of 2
is not merely the result of the presence of two iodine centers, but
very likely the consequence of bidentate binding.
Scheme 2. Michael addition of 1-methylindole 8 to trans-β-crotonophenone 10
as benchmark reaction
Sodium traces and BArF
by the fact that NaBArF
as the active species can be ruled out
gave only 26% conversion and that
Scheme 1. Synthesis of XB donor 2 via salt metathesis.
4
4
tetramethyl ammonium (TMA) BArF
was inactive. HB donor 7
In the past, triflate counterions often hindered the activity of XB
donors by outcompeting neutral Lewis bases.[7c, f, 19] To overcome
this blockage and to drastically increase the solubility of 1, non-
4
was also inactive.[32] In a direct comparison with our so far
strongest XB donor 6, only 41% product was formed after 1 h and
full conversion was not achieved within 12 h (Figure 4).
coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF
)
4
counterions were introduced via our recently published method,[22]
which provided XB donor 2 as a dietherate complex with 35%
yield (Scheme 1).
With this promising XB donor in hand, our goal was to determine
its activity in a series of increasingly challenging transformations
and to compare its results to several reference compounds
2
3
4
6
1
(10 mol%)
(10 mol%)
2 (1 mol%)
3 (20 mol%)
5 (10 mol%)
7 (10 mol%)
10 mol% TMABArF
(10 mol%)
(10 mol%)
0 mol% NaBArF
1
00
(
Figure 3): monodentate variant 3 as well as its derivatives with
8
6
4
2
0
0
0
0
0
one (4) or both (5) electrophilic axes blocked,[19] our currently
strongest XB donor 6,[7d] and a representative hydrogen bonding
(
HB) organocatalyst 7.[29]
0
2
4
6
8
10
12
t [h]
Figure 4. Yield-vs.-time profile of the Michael addition between 1-methylindole
and trans-β-crotonophenone 9 in the presence of different halogen bond
8
donors.
In parallel, DFT calculations (M06-2X-D3[33] def2-TZVP(D)[34]
)
Figure 3. Lewis acidic organocatalysts employed as reference compounds in
were employed to obtain the transition state of the reaction
involving catalyst 2. Its structure clearly confirms bidentate XB
between the carbonyl group and the two iodines, with C-I•••O
distances of 2.56 Å and angles of 159° (Figure 5). The
corresponding Gibbs free energy of activation is 13 kcal/mol
(compared to 22 kcal/mol for the transition state involving catalyst
6, see SI).
this study.
As a first benchmark reaction we focused on the Michael addition
reaction between 1-methylindole 8 and trans-β-crotonophenone 9
(
Scheme 2). which is known to be less reactive towards hidden
Brønsted acids.[ It can, however, be successfully catalyzed
through XB with molecular iodine[30] and cationic iodine(I)
donors.[7e, g, 31] In contrast to earlier studies, we started our initial
experiments with a 10 mol-% catalyst loading and already
observed a strong activity of XB donor 2, yielding 74% of product
30]
10 after 1 hour and full conversion after 9 hours (Figure 4).
Reducing the catalyst loading to only 1 mol-% still provides a
satisfying conversion of 62% after 12 hours. Comparison
experiments with monodentate iodolium compounds 3, 4, and 5
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almost 50 h with a catalyst loading of 20 mol-% in our earlier
study).[7g] This stark difference in activity vividly illustrates how
much more powerful the bidentate iodine(III)-based XB donor is
compared to a similarly preorganized iodine(I) variant. Hidden
sodium catalysis and any counterion effect can once again be
excluded, as NaBArF and TMA BArF
are inactive as well. The
4
4
same is true for HB organocatalyst 7 and for molecular iodine, a
strong XB donor.[9]
Just like for the Michael reaction discussed above, DFT
calculations on the likely transition state also yielded a structural
model featuring bidentate coordination of the catalyst to one
oxygen of the nitro group (Figure 7). The C-I•••O distances are
2.62 Å and 2.69 Å, with XB angles of 158-160°. The associated
Gibbs free energy of activation is 17 kcal/mol (while, interestingly,
these orientating calculations yield a barrier of only 13 kcal/mol
for the transition state involving catalyst 6).
Figure 5. Transition state of the Michael addition reaction involving XB donor 2,
as obtained by DFT calculations. Graphic generated with CYLview.[35]
After this successful carbonyl activation, we were next interested
in the nitro-Michael reaction between 5-methoxyindole 11 and
nitrostyrene 12, which we had used before as benchmark
(
Scheme 3).[7g, 36]
Scheme 3. Nitro-Michael addition reaction between 5-methoxyindole 11 and
nitrostyrene 12 in the presence of different XB donors.
Even under decidedly more challenging conditions than in our
earlier study (lower overall concentration, 1:1 ratio of starting
materials, lower catalyst loading of 5 mol-%),[7g] 83% product
Figure 7. Transition state of the nitro-Michael addition reaction involving XB
donor 2, as obtained by DFT calculations. Graphic generated with CYLview.[32]
formation was already observed after only 1 h and the reaction
was completed after 3 h when XB donor 2 was used (Figure 6).
Again, just 1 mol-% of XB donor 2 still yielded 55% of product 13
Finally, we focused on a Diels-Alder reaction to further illustrate
the catalytic activity of catalyst 2, once again opting for a
challenging case. Thus, in contrast to our earlier benchmark
reaction between methyl vinyl ketone 15 and 10 equivalents of
cyclopentadiene,[7e, g, 19] we now employed just one equivalent of
less reactive cyclohexadiene 14 as diene (Scheme 4).
1
after 8 hours. In H-NMR titration experiments, binding constants
for the adduct of catalyst 2 and substrate 12 of K = 29 M-1 as well
as for the adduct of the same catalyst and product 13 of K = 18 M-1
were revealed.[37]
2
3
5
7
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
2 (1 mol%)
4 (5 mol%)
6 (5 mol%)
NaBArF4 (5 mol%)
Iodine (5 mol%)
TMABArF (5 mol%)
blank
1
00
Scheme 4. Diels-Alder reaction between 1,3-cyclohexadiene 14 and methyl
vinyl ketone 15 with various XB donors.
8
6
4
2
0
0
0
0
0
With 30 mol-% of catalyst 2, 73% of product 16 was formed after
12 h (Figure 8). The use of similar amounts of monodentate
iodolium salts 3, 4 and 5 as well as of bidentate iodine(I) donor 6
or of molecular iodine led to no reaction (Figure 8).[38]
Acid traces were also excluded as potentially catalytically active
species: first, slow decomposition of the catalysts was ruled out
by a repeated-addition experiment, in which portions of starting
0
2
4
6
8
Time [h]
Figure 6. Yield-vs.-time profile for the nitro-Michael addition between 5-
methoxyindole 11 and nitrostyrene 12 with various catalysts.
materials 14 and 15 were added to the reaction mixture again
after 18 h. The resulting similar reaction profile[39] indicates that
no catalytically active species was generated over time. Second,
we observed that addition of HOTf to 1,3-cyclohexadiene lead to
Monodentate iodolium salts 3, 4, and 5 are inactive, as is the
bidentate XB donor 6 (which lead to 40% product formation after
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quick decomposition. Furthermore, the activity of catalyst 2 can
be completely suppressed by pre-mixing it with tetrabutyl
ammonium chloride (TBACl), presumably by the chloride blocking
the binding site of the catalyst.[19] In addition, hidden Na catalysis
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as (neutral) organocatalyst induced no reaction. With the
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3
[
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[
3
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change in concentration.
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[
The authors gratefully acknowledge support by the Fonds der
Chemischen
Industrie.
Funded
by
the
Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation)
under Germany's Excellence Strategy - EXC 2033 - 390677874 –
RESOLV.
[
[
28] This may be considered as a rare case of bifurcated halogen bonding
(
see e.g. N. Kuhn, M. Richter, M. Steimann, M. Ströbele, K. Sweidan, Z.
Anorg. Allg. Chem. 2004, 630, 2054).
Keywords: halogen bonding • organocatalysis • noncovalent
interactions • hypervalent iodine • Diels-Alder cycloaddition
[
29] A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407.
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Angewandte Chemie International Edition
10.1002/anie.202013172
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Abstract: The first application of
a
Flemming Heinen, Dominik Reinhard,
Elric Engelage, Stefan M. Huber*
bidentate iodine(III)-based halogen
bond donor as organocatalyst is
presented.
reactions, it markedly outperforms
classical” iodine(I)-based noncovalent
In
three
benchmark
A bidentate iodine(III)-based halogen-
bond donor as a powerful
organocatalyst
“
organocatalysts. The bidentate mode of
activation as well as the crucial
relevance of halogen bonding are
confirmed by comparison experiments.
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