Chalcogen-Bonding Catalysis: From Neutral to Cationic Benzodiselenazole Scaffolds

Article abstract of DOI:10.1002/hlca.201800075

Benzodiselenazoles (BDS) are emerging as privileged structures for chalcogen-bonding catalysis in the focal point of conformationally immobilized σ holes on strong selenium donors in a neutral scaffold. Whereas much attention has been devoted to work out

Full text of DOI:10.1002/hlca.201800075

(1 of 5) e1800075
COMMUNICATION
Chalcogen-Bonding Catalysis: From Neutral to Cationic
Benzodiselenazole Scaffolds
Sebastian Benz, Celine Besnard, and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland,
e-mail: stefan.matile@unige.ch
Benzodiselenazoles (BDS) are emerging as privileged structures for chalcogen-bonding catalysis in the focal point
of conformationally immobilized r holes on strong selenium donors in a neutral scaffold. Whereas much attention
has been devoted to work out the advantages of selenium compared to the less polarizable sulfur donors, high
expectations concerning bidentate, rigid, and neutral scaffolds have been generated with little experimental support.
Here we report design, synthesis and evaluation of the necessary catalysts to confirm that i) bidentate BDS are more
effective than their monodentate analogs, ii) conformationally immobilized scaffolds are more effective than more
flexible ones, iii) cationic BDS scaffolds are more effective than neutral ones, and iv) in dicationic-bidentate BDS,
contributions from chalcogen-bonding dominate possible contributions from ion-pairing catalysis. These conclusions
result from rate enhancements found for a Ritter-type anion-binding reaction and an X-ray crystal structure of
dicationic BDS with a triflate anion bound with highest precision in the focal point of the r holes.
Keywords: chalcogens, chalcogen-bonding catalysis, supramolecular chemistry, unorthodox interactions, selenium-
containing heterocycles, heterocycles.
Figure 1,a).[10 – 13] They have been studied extensively
in crystal engineering and for intramolecular confor-
Introduction
The integration of new interactions into functional sys- mational control in solution, including prominent use
tems is of general interest, because it promises access in medicinal chemistry and pioneering applications in
to new structures with new functions.[1][2] This focus on covalent catalysis.[11 – 17] The use of intermolecular
unorthodox interactions at work accounts for the recent chalcogen bonds in functional systems in solution is rare
discovery of catalysis with anion-p interactions,[3] halo- and recent,[13 – 22] non-covalent chalcogen-bonding
gen bonds,[2] chalcogen bonds,[4] and pnictogen catalysis has been introduced only last year.[4][23][24]
bonds,[5] and the renewed attention to their conven- The key to success was the idea that the somewhat
tional counterparts such as cation-p interactions.[6] The awkwardly ‘hidden’ position of the r holes on the side
large, polarizable, almost directionless p surface offered of chalcogen-bond donors turns into an advantage as
by anion-p interactions appears ideal to stabilize anio- soon as transition-state recognition in the focal point
nic transition states that involve charge displacements of two adjacent donors is considered.[4] Dithiophenes
over longer distances, e.g., cascade cyclizations.[7 – 9] (Figure 1,d) were taken as starting point to think about
The advantages of r-hole interactions,[10 – 13] the chalcogen-bonding scaffolds for the recognition of
unorthodox counterpart of hydrogen bonds, appear electron-rich motifs in ground and transition state that
almost complementary: More hydrophobic and direc- would reflect the fundamental general versatility of
tional than hydrogen bonds, they should be ideal for classics such as metal-binding bipyridines (Figure 1,b)
high-precision catalysis in apolar media.
or hydrogen-bonding bipyrroles (Figure 1,c). However,
Originating from anti-bonding r* orbitals, chalco- in dithiophenes, the bite angle Φ3 = 34° was too
gen bonds extend linearly from the covalent bonds small for binding in the focal point of the r holes (Fig-
(bond angle Φ1 ~ 180°) and thus appear on the side ure 1,d). This bite angle was adjusted to Φ3 = 45° by
of the chalcogen atom (bond angle Φ2 ~ 70°, adding a single-atom sulfur bridge between the two
DOI: 10.1002/hlca.201800075
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Helv. Chim. Acta 2018, 101, e1800075
Scheme 1. Structure and schematic synthesis of cationic
chalcogen-bonding catalysts. a) MeOTf, DCE, lW, 100 °C, 8 h,
90%. b) 1. HCOOH/Ac2O, 40 °C, 1 h; 2. 6, 0 °C to r.t., 1 h, quant.;
3. Et3N, POCl3, THF, r.t., 4 h, 63%; 4. Se, Et3N, CHCl3, reflux, 14 h,
63%. c) 1. NaH, THF, 0 °C, 30 min, quant.; 2. CuI, 1,10-phenan-
throline, Cs2CO3, DME, reflux, 2 h, 91%; 3. MeOTf, DCE, 50 °C,
2 h, 74%.
Figure 1. Concept and evolution of chalcogen-bonding cataly-
sis. a) Schematic anion binding to thiophenes, with ideal bond
angles Φ1 ~ 180° and Φ2 ~ 70°. b) Cation binding by 2,20-bipyri-
dines. c) 2,20-Bipyrroles with hydrogen-bonded anions. d) 2,20-
Dithiophenes (Φ3 = 34°, Φ1 = 149°), e) DTTs (Φ3 = 45°, Φ1
~
180°), and f) BDS (Φ3 = 45°, Φ1 ~ 180°) with chalcogen-bonded
anions. g) Previously reported chalcogen-bonding catalysts.[23][24]
bis(2-selanylbenzimidazolium) (SBI) catalysts 2 have been
reported last year by the Huber group (Figure 1,g).[23]
Cationic chalcogen-bond donors are intriguing because
access to deepened r holes comes at the cost of
possible complications from competitive ion pairing,
interference from counterions, and poor solubility.[27] In
this short communication, we report design, synthesis
and evaluation of the catalysts 3 and 4 that were
needed to clarify these open questions (Scheme 1).
heterocycles. The result were dithieno[3,2-b:20,30-d]
thiophenes (DTTs) with an ideal Φ3 = 45° (Figure 1,
e).[4] However, the formal substitution of the sulfur
donors in DTTs with stronger selenium donors again
turned the bite angle out of focus, this time becoming
too large (Φ3 = 53°) because of the long C–Se bonds.
This mismatch was corrected to Φ3 = 45° by replacing
the single-atom bridge in DTTs with a double-atom
bridge in benzo[1,2-d:4,3-d’]di([1,3]selenazole)s (BDS,
Figure 1,f).[24]
BDS are a new motif. However, benzomonoselena-
zoles (BMS) have been explored previously with
regard to their optoelectronic properties and possible
applications in the materials sciences.[25][26] In the
most active chalcogen-bonding BDS catalyst reported
so far, i.e. 1, the BDS scaffold is decorated with elec-
tron-withdrawing cyano and sulfone acceptors to dee-
pen the r holes on the endocyclic Se donors
(Figure 1,g).[24] The superiority of selenium compared
to the less polarizable sulfur donors for chalcogen-
bonding catalysis has been clearly demonstrated.[24]
However, the functional relevance of other characteris-
tics of the BDS scaffold, that is i) bidentate binding in
the focal point of proximal r holes, ii) conformational
rigidity, and iii) the possibility to easily inject posi-
tive charges into the selenazole heterocycles by
methylation, has never been clarified experimentally.
With regard to cationic chalcogen-bond donors,
conformationally more flexible chalcogen-bonding
The dicationic-bidentate BDS catalyst
obtained in 90% yield by methylation of the previ-
ously reported[24] BDS catalyst
with MeOTf
3 was
5
(Scheme 1). Relatively harsh conditions, i.e., microwave
irradiation at 100 °C for eight hours, were needed
because methylation required deplanarization of the
peripherally crowded BDS backbone (vide infra). The
monodentate-cationic BMS counterpart 4 was synthe-
sized from 2-bromoaniline 6 in six steps, with a cop-
per-catalyzed cascade cyclization of isoselenocyanate
7 with thiophenol 8 as the key transformation
(Schemes 1, S1).
The activity of catalysts 1, 3, and 4 was assessed
with the Ritter-type solvolysis of benzhydryl bromide
9 that was previously used by the Huber group to
characterize catalyst 2 (Figure 2).[23] This reaction is
well suited to test cationic catalysts, since it is acid
insensitive and therefore only marginally affected by
the possible presence of residual traces of acids from
the counterion, e.g. HOTf.[23] Chalcogen-bonding
catalysis of the solvolysis of benzhydryl bromide 9 in
acetonitrile operates by transition-state recognition of
the rate-limiting elimination of bromide. Reaction of
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Helv. Chim. Acta 2018, 101, e1800075
withdrawing substituents in 1 (kcat/kuncat = 17) is less
effective than with the two endocyclic positive
charges in 3 (kcat/kuncat = 36).
Under identical conditions, kcat/kuncat = 34 has
been reported for the syn atropisomer of the biden-
tate SBI activator 2.[23] With kcat/kuncat = 23, the mon-
odentate anti atropisomer of 2 was less active. In
comparison, the monodentate anti SBI 2 was clearly
more active than monodentate BMS activator 4 (kcat
/
kuncat = 23 vs. 10), whereas bidentate syn SBI 2 was
slightly less active than bidentate DBS 3 (kcat/kuncat
= 36 vs. 34).[23] This higher relative increase in activity
from monodentate to bidentate benzoselenazole com-
pared to SBI scaffolds supported the importance of
conformational immobilization of the r holes to maxi-
mize transition-state stabilization in their precisely
localized focal point.
The central challenge with cationic chalcogen-
bonding catalysts besides the presence of counteri-
ons are possible contributions from ion-pairing
catalysis. In the present example, the bromide leav-
ing group in substrate 9 could be activated next to
one of the cationic nitrogens in 3 rather than in the
Figure 2. Initial velocity of the solvolysis of benzhyrdyl bromide
9 (16.5 mM) by wet (~1.6 equiv. H2O), deuterated acetonitrile in
the presence of chalcogen-bond activators 4 (1 equiv., ◇; 2
equiv., M), 3 (●), 1 (○) and without activator (▼), at room tem-
perature.
the resulting carbocation with acetonitrile and hydrol- focal point of the chalcogen-bond donors. The crys-
ysis of the nitrilium intermediate by traces of water tal structure1 of catalyst 3 suggested that these con-
in the solvent affords the N-benzhydryl acetamide cerns are not justified (Figure 3). One of the triflate
10. In this reaction, chalcogen-bonding catalysts are anions was found in the focal point of the r holes,
used in stoichiometric amounts because of their pos- with chalcogen bonds that excel with short bonds
ꢀ
sible inactivation by the eliminated bromide anion of maximal 2.90 A and nearly ideal bond angles of
and thus act formally as activators rather than as cat- minimal 167.8°. In the crystal structure, only the sec-
alysts. However, the previously confirmed function of ond triflate ion paired with one of the cationic nitro-
1 and 5 to catalyze transfer hydrogenation of gens (not shown). Both aryl sulfides are in syn
quinolines and imines justifies the use of the term conformation with respect to the selenium donors,
catalyst.[24]
without contact to the anion. Peripheral crowding
Rate enhancements by chalcogen-bonding cata- forces the methyl groups out of plane. To minimize
lysts were determined based on molecular concentra- contact, they naturally prefer an all-trans conforma-
tions, independent of the number of chalcogen-bond tion. This deplanarization explained the harsh condi-
donors per molecule. Following the standard Huber tions needed for methylation of the neutral
protocol,[23] linear fitting of the initial rate of pro- precursor 5.
duct formation revealed
a
rate enhancement
In summary, we conclude that in chalcogen-
kcat/kuncat = 36 for the dicationic-bidentate BDS activa- bonding catalysts with comparable selenium donors,
tor 3 (Figure 2, ● vs. ▼). This rate enhancement dicationic-bidentate are better than neutral-bidentate
exceeded the kcat/kuncat = 8 and kcat/kuncat = 10 mea- scaffolds,
neutral-bidentate
are
better
than
sured with one and two equivalents of the cationic- cationic-monodentate scaffolds, chalcogen-bonding
monodentate BMS activator 4, respectively (Figure 2,
1Crystallographic data for 3 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC-1846776. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/da
ta_request/cif, by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
◇M). The bidentate-neutral BDS activator 1 was with
kcat/kuncat = 17 (Figure 2, ○) more active than the
cationic-monodentate BMS activator 4 (Figure 2, ◇),
but clearly less active than the dicationic-bidentate
BDS activator 3, despite the presence of withdrawing
cyano and sulfone acceptors (Figure 2, ●). In other
words, deepening of the r holes in the essentially
inactive[24] precursor
5
with the four electron- 441223 336033.
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