Carbon–Halogen Bond Activation by Selenium-Based Chalcogen Bonding

Article abstract of DOI:10.1002/anie.201704816

Chalcogen bonding is a little explored noncovalent interaction similar to halogen bonding. This manuscript describes the first application of selenium-based chalcogen bond donors as Lewis acids in organic synthesis. To this end, the solvolysis of benzhydr

Full text of DOI:10.1002/anie.201704816

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Accepted Article
Title: Carbon-Halogen Bond Activation by Selenium-Based Chalcogen
Bonding
Authors: Patrick Wonner, Lukas Vogel, Maximilian Düser, Luís Gomes,
Florian Kniep, Bert Mallick, Daniel B Werz, and Stefan
Matthias Huber
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10.1002/anie.201704816
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Carbon-Halogen Bond Activation by Selenium-Based Chalcogen
Bonding
Patrick Wonner,[a] Lukas Vogel,[a] Maximilian Düser,[a] Luís Gomes,[a] Florian Kniep,[a] Bert Mallick,[a]
Daniel B. Werz,[b] and Stefan M. Huber[a]*
Abstract: Chalcogen bonding is a little explored non-covalent
interaction similar to halogen bonding. This manuscript describes the
first application of selenium-based chalcogen bond donors as Lewis
acids in organic synthesis. To this end, the solvolysis of benzhydryl
chalcogen bond donor and the nonbonding lone pair of the
Lewis base. Finally, dispersion contributions will also be relevant
for heavier chalcogens.
Due to its electronic origin, chalcogen bonding is highly
directional,[5,6] as reasonably strong chalcogen bonding requires
R-Ch…LB angles of approximately 180°. Even though it is
typically weaker than halogen bonding,[7] chalcogen bonding
features two distinct advantages over the latter: firstly, the
second substituent R’ on the chalcogen atom - orientated at 90°
relative to the Ch…LB interaction - interacts more directly with
the substrate than the backbone R of halogen bond donors R-X.
bromide served as
a halide-abstraction benchmark reaction.
Chalcogen bond donors based on a bis(benzimidazolium) core
provided rate accelerations versus background reactivity in the order
of 20-30. Several comparison experiments provide clear indications
that chalcogen bonding is the origin of the observed activation. The
performance of the chalcogen bond donors is superior to that of the
related brominated halogen bond donor.
Secondly, if both substituents
R and R’ are sufficiently
electronegative, two perpendicular electrophilic axes on the
chalcogen substituent are present.
In recent years, the application of previously little-explored
interactions like anion-[1] and halogen bonding[2] in solution has
received increased interest. Closely related to halogen bonding
is chalcogen bonding, i.e. the attractive interaction between an
electrophilic chalcogen substituent Ch (S, Se, or Te) and Lewis
bases LB (Figure 1).[3] Such Lewis acids R/R’-Ch are typically –
albeit somewhat confusingly – called chalcogen bond donors
(despite their function as electron acceptors).
In the solid state, chalcogen bonding has been applied in some
few cases to construct supramolecular assemblies like
nanotubes,[8a,b] nanosheets,[8c] wires,[8d] and macrocycles.[8e] In
solution, fundamental studies and applications are arguably
even more rare and focus mostly on anion recognition.
Investigated systems include a mixed telluronium/boron Lewis
acid,[9a] benzotelluradiazoles as monodentate receptors[9b] and
tellurophene derivatives as bidentate ones.[9c] Very recently,
Beer et al. also reported the use of seleno- and
telluriumtriazol(ium) motifs in anion-binding rotaxanes.[10] Even
though sulfur-based chalcogen bond donors are expected to
form weaker interactions than selenium- or tellurium-based ones,
an appropriately designed bidentate dithienothiophene (DTT)
derivative has been used by Matile et al. for anion transport.[11]
Since Lewis acids based on “unconventional” weak interactions
like anion-[12] and halogen bonding[13] have by now been
introduced in organic synthesis and organocatalysis, a similar
approach seems feasible for chalcogen bonding. The few
currently known examples related to this concept focus almost
exclusively on intramolecular binding as a tool to rigidify
structural motifs.[14]
In contrast, the first chalcogen bonding based organocatalysis
by the intermolecular coordination and activation of a substrate
has recently been published by Matile.[15] In this case, DTT
derivatives catalyzed the reduction of quinolone derivatives.
Herein, we present the first application of selenium-based
chalcogen bond donors as noncovalent activators, utilizing a
C-X activation (“anion binding”) benchmark reaction.[16] These
kind of proof-of-principle studies pose two main challenges: i)
since chalcogen bonds are rather weak, other interactions will
likely also contribute and it is difficult to ascribe the action of an
activator to chalcogen bonding as main cause and ii) it is often
difficult to rule out the action of impurities, most importantly
hidden traces of acid.
Figure 1. Definition of chalcogen bonding (LB = Lewis base).
Several components likely contribute to the overall interaction
energy: similarly to halogen bonding, the electronic distribution
of heavier chalcogen atoms is anisotropic, with reduced electron
density in the elongation of the R-Ch axes. In suitably polarized
compounds, a region of positive electrostatic potential (“-
hole”)[4] is formed, which interacts favorably with the negatively
polarized Lewis base. Furthermore, electronegative groups R
lower the * orbital of the R-Ch bond and increase its coefficient
on the Ch substituent. Thus, chalcogen bonding may also be
described as an n* charge transfer interaction[5] between the
[a]
[b]
P. Wonner, L. Vogel, M. Düser, Dr. L. Gomes, Dr. F. Kniep, Dr. B.
Mallick, Prof. Dr. S. M. Huber
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum
Universitätsstraße 150, 44801 Bochum (Germany)
E-mail: stefan.m.huber@rub.de
Prof. Dr. D. B. Werz
Institut für Organische Chemie, TU Braunschweig
Hagenring 30, 38106 Braunschweig
As
a consequence, a relatively simple test reaction, the
solvolysis of benzhydryl bromide 1 in wet acetonitrile, was
chosen (Scheme 1). This transformation, which we already
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201704816
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applied in fundamental studies on halogen bonding, was shown
to be immune to hidden acid catalysis.[16] In addition, it has
virtually no background reaction at room temperature and is
easy to follow via 1H NMR spectroscopy.
4N-Me or 4N-Oct, selenation was achieved with caesium carbonate
and elemental selenium.[19] In both cases, the resulting
selenated isomers could be separated via column
chromatography (4N-Me: 38% syn, 62% anti; 4N-Oct: 26% syn, 74%
anti). Subsequent alkylation with methyl, octyl or isopropyl triflate
proceeded with good to excellent yields and provided the
desired cationic chalcogen bond donors (see SI). All chalcogen
bond donors are stable under air and moisture and show no
signs of decomposition in acetonitrile solution even after three
months (in 1H and 19F NMR).
The X-ray structural analysis of compound anti-6N-Me/Se-Me
included two dications and four triflates in the unit cell (Figure 2).
Scheme 1. Anion-binding benchmark reaction.
For the design of strong chalcogen bonding based activator
candidates, we decided to rely on cationic backbones R in order
to achieve a strong polarization of (at least one) R-Ch bond.[17]
More precisely, the bis(benzimidazolium)-based backbone
structure of 4 (Scheme 2) was selected since the corresponding
halogen bond donor had shown a relatively strong Lewis
acidity.[18] The trifluoromethyl group in these compounds
prevents rotation of the benzimidazolium groups and allows
monitoring via 19F NMR. As chalcogen, selenium was selected,
since it should provide stronger Lewis acidity than sulfur, but be
less prone to decomposition than tellurium. Ideally, a bidentate
coordination of substrates by chalcogen bond donors 4 is
aspired, as is predicted by gas-phase calculations (see SI).
Since selenium is smaller than iodine, it remains uncertain
whether this binding motif can indeed be realized in solution.
Finally, simple alkyl groups were introduced as second
substituents on the chalcogen: octyl or isopropyl for good
solubility, methyl for crystallization studies.
Figure 2. X-ray structural analysis of anti-6N-Me/Se-Me. One ion pair of two in the
unit cell is shown (ellipsoids at 50% probability). Selected bond lengths [Å] and
angles [°]: C-Se2 = 1.891, C-Se1 = 1.900, C-Se2-O2 = 163, C-Se1-O1 = 173.
All four selenium centers feature
a chalcogen bond (in
elongation of the Cbenzimidazolium-Se bond) to oxygen atoms of
triflate. The corresponding Se…O distances range from 2.94 to
3.24 Å, all markedly below the sum of the van-der-Waals radii of
both elements (3.42 Å).[20] The C-Se…O angles (163° to 173°)
are in general agreement with the expected linearity, with one
slight exception (151°), which is likely due to additional packing
effects. Overall, the crystal structure clearly confirms the
expected * acidity of the carbon-selenium bonds.
With these promising findings in hand, several activator
candidates were tested in the benchmark reaction mentioned
above (Scheme 1). All reactions were reproduced at least twice
with only minor variations. In all cases, a clean transformation to
amide 2 was observed. Even after 140 h, the background
reactivity amounts to only 10% yield of 2 (Table 1, entry 1).
Scheme 2. Synthesis of chalcogen bond donors; i) R-OTf, CH2Cl2 (R = Me,
Oct); ii) Se, Cs2CO3, MeOH; iii) R-OTf, CH2Cl2 (R = Me, Oct, iPr). Selected
yields: syn/anti-4N-Oct 84%, syn-5N-Me 80%, anti-5N-Me 87%, syn-5N-Oct 33%, anti-
5N-Oct 63%, syn-6NOct/Se-iPr 95%, anti-6NOct/Se-iPr 90%, see also SI.
Table 1. Effect of various chalcogen bond donors and reference compounds
on the anion-binding benchmark reaction of Scheme 1.
Entry
Activating
reagent
Equiv.[a]
Yield [%][b]
The synthesis of the chalcogen bond donors is depicted in
Scheme 2. Starting from an (inseparable) syn/anti mixture of
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10.1002/anie.201704816
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COMMUNICATION
selanylalkyl group must constitute the active site, and the X-ray
structural analysis of anti-6N-Me/Se-Me as well as the DFT
calculations (see SI) clearly show chalcogen bonding as its
binding mode.[21]
1
---
---
10
2
syn/anti-4N-Oct
syn-6N-Oct/Se-iPr
anti-6N-Oct/Se-iPr
syn-5N-Oct
iPrBr
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
11
3
64
The corresponding anti-isomer of 6N-Oct/Se-iPr was somewhat less
active (45 % yield of 2, entry 4), but the difference to the syn-
isomer was not very strong. This seems to indicate that syn-
6N-Oct/Se-iPr does not bind to bromide in a clean bidentate fashion,
as a more pronounced effect might be expected in this case.
Subsequently, several simple monodentate benzimidazolium
derivates (Figure 3) were used as potential activating reagents,
to further elucidate any effect of the backbone structure of anti-
6N-Oct/Se-iPr on the activity of the individual seleno-
benzimidazolium moieties. Two equivalents of these species
were used in the test reactions to provide the same number of
active centers as with the bifunctional chalcogen bond donors
described before.
4
45
5
< 5[c]
< 5
6
7
7H
16
8
8
< 5[c]
34
9
9Se-Oct
10
11
12
13
9Se-iPr
45
7I
48[d]
> 95%[e]
35%
syn-10I
syn-10Br
[a] Equivalents of activating reagent (relative to 1). [b] Yield of 2 after 140 h
at room temperature according to 1H NMR analysis (see the Supporting
Information). [c] Low solubility in acetonitrile. [d] Yield after 96 h. [e]
Quantitative yield of 2 after 24 h.
Figure 3. Further reference compounds (X = H, Br, I; R = Oct, iPr).
Next, several potentially bidentate activating reagents were
employed. The (so far inseparable) syn/anti-mixture of non-
selenated reference compound 4N-Oct resulted in only 11%
product formation (Table 1, entry 2) and thus provided no
noticeable activation of 1.
Similarly to the previous findings, the selenated derivates 9Se-Oct
(34% yield, entry 9) and 9Se-iPr (45% yield, entry 10) were
markedly more active than the non-selenated reference
compound 7H (16%, entry 7) and the non-alkylated precursor 8
(< 5%, entry 8). Thus, since the activity of two equivalents of
9Se-iPr is identical to that of one equivalent of anti-6N-Oct/Se-iPr
there seems to be no additional effect of the backbone of the
latter on its chalcogen bonding subunits.
In contrast, all selenated (cationic) derivatives induced a marked
increase in the yield of 2. Compound syn-6N-Oct/Se-Me, for instance,
lead to approx. 60% yield after 96 h. However, NMR spectra of
the reaction showed clear signs of activator decomposition by
dealkylation of the selenium center, as formation of MeBr was
observed. Titration experiments with bromide confirmed that this
chalcogen bond donor is not stable under the reaction conditions.
The same is true, albeit to a somewhat lesser extent, for the
octylated variant syn-6N-Me/Se-Oct and thus both were not
considered further. Since dealkylation will likely occur via an SN2
mechanism, we reasoned that a secondary alkyl substituent on
selenium should provide more stability. Indeed, activator
candidate syn-6N-Oct/Se-iPr showed only minor signs of
decomposition (4% after 140 h according to 19F NMR) and was
thus considered suitable for further activation experiments.
Amide 2 was formed with 64% yield (Table 1, entry 3; for a
stackplot see SI). The NMR spectra indicate that the slight
decomposition of syn-6N-Oct/Se-iPr over time is again due to
dealkylation with formation of isopropyl bromide. To rule out any
activity of syn-5N-Oct and iPrBr - which would have to be
catalytic -, both were also tested and provided less than 5%
yield of product (Table 1, entries 5 and 6).
,
Finally, a direct comparison of the activation by chalcogen
bonding with the already established one by halogen bonding
was aspired. To this end, closely related halogenated analogues
were also used, and in the case of 7I (48% yield after 96 h, entry
11), the performance was somewhat superior to the one of 9Se-iPr
The difference was more pronounced for the bidentate variants,
as syn-10I lead to quantitative product formation after 24 h.[22]
Part of this difference might be due to a less strained bidentate
binding of bromide by the iodinated Lewis acid. However, an
arguably more fair comparison is the one to the halogen of the
same period, and syn-10Br is indeed even slightly less active
.
(35 %, entry 13) than syn-6N-Oct/Se-iPr
.
Yield-versus-time profiles for selected reactions are presented in
Figure 4. Based on the initial slopes of product formation, it can
be estimated that the reaction rate increases by about one order
of magnitude by syn-10Br compared to the background (krel = 9).
The rate acceleration by the chalcogen bond donors, in turn, is
about twice (anti-6N-Oct/Se-iPr, krel = 23) or three times (syn-6N-
Oct/Se-iPr, krel = 34) that of syn-10Br.
All findings presented so far provide strong indications that the
activity of syn-6N-Oct/Se-iPr is based on chalcogen bonding: acid
catalysis can be ruled out in this reaction and the otherwise
identical non-selenated compound (which should form at least
as strong anion- interactions) is completely inactive. Thus, the
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[3]
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Am. Chem. Soc. 2006, 128, 2666-2674; b) W. Nakanishi in Handbook
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Nat. Commun. 2016, 7, 11299.
Figure 4. Yield-versus-time profile of selected reactions.
In conclusion, the first intermolecular use of selenium-based
chalcogen bond donors as Lewis acids in organic synthesis was
presented. Using a suitable benchmark reaction for halide
binding reactivity and several comparison experiments, strong
indications for chalcogen bonding as the actual mode of action
were obtained - most notably the fact that the corresponding
non-selenated reference compound was inactive. Even if the
observed effect is less strong than the activity of bidentate
iodine-based halogen bond donors, further detailed
investigations on the use of chalcogen bonding in solution will
likely provide the basis for more sophisticated mixed catalyst
systems, in which chalcogen bonding could play an important
role.
[9]
a) H. Zhao, F. P. Gabbaï, Nat. Chem. 2010, 2, 984-990; b) G. E.
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P. D. Beer, J. Am. Chem. Soc. 2017, 139, 3122-3133.
[11] S. Benz, M. Macchione, Q. Verolet, J. Mareda, N. Sakai, S. Matile,
J. Am. Chem. Soc. 2016, 138, 9093-9096.
[12] L. Liu, Y. Cotelle, J. Klehr, N. Sakai, T. R. Ward, S. Matile, Chem. Sci.
2017, 8, 3770-3774 and literature cited therein.
[13] D. Bulfield, S. M. Huber, Chem. Eur. J. 2016, 22, 14434-14450.
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[15] S. Benz, J. López-Andarias, J. Mareda, N. Sakai, S. Matile, Angew.
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Acknowledgements
This project has received funding from the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation programme (grant agreement No
638337).
[18] S. H. Jungbauer, S. M. Huber, J. Am. Chem. Soc. 2015, 137, 12110-
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[19] K. B. Bhabak, K. Sathesshkumar, S. Jayavelu, G. Mugesh, Org. Biomol.
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[20] A. Bondi, J. Phys. Chem. 1964, 68, 441.
Keywords: chalcogens • noncovalent interactions • Lewis acids
• chalcogen bonding • solvolysis
[21] In further experiments to rule out active impurities, different batches of
elemental selenium were used and different materials for column
chromatography were employed, with virtually identical results in all
cases.
[1]
[2]
See, for example: a) Y. Zhao, Y. Cotelle, N. Sakai, S. Matile, J. Am.
Chem. Soc. 2016, 138, 4270-4277; b) M. Giese, M. Albrecht, K.
Rissanen, Chem. Commun. 2016, 52, 1778-1795.
[22] Titration experiments with NOct4Br in acetonitrile also showed that syn-
6N-Oct/Se-iPr binds weaker to bromide (K = 340 M-1) than syn-10I (K =
3.5 · 106 M-1, ref. [18]), see SI.
a) G. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A. Priimagi, G. Resnati,
G. Terraneo, Chem. Rev. 2016, 116, 2478-2601; b) M. Erdélyi, Chem.
Soc. Rev. 2012, 41, 3547-3557.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Activation, se(en) from a different
angle! Chalcogen bond donors
(chalcogen-based Lewis acids)
P. Wonner, L. Vogel, M. Düser, L.
Gomes, F. Kniep, B. Mallick, D. B. Werz,
S. M. Huber*
provide rate accelerations in a halide
abstraction benchmark reaction in the
order of 20-30. Several comparison
experiments provide clear indicactions
that chalcogen bonding is the origin of
the observed activation.
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Carbon-Halogen Bond Activation by
Selenium-Based Chalcogen Bonding
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Author(s), Corresponding Author(s)*
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