Catalysis with chalcogen bonds: Neutral benzodiselenazole scaffolds with high-precision selenium donors of variable strength

Article abstract of DOI:10.1039/c7sc03866f

The benzodiselenazoles (BDS) introduced in this report fulfill, for the first time, all the prerequisites for non-covalent high-precision chalcogen-bonding catalysis in the focal point of conformationally immobilized σ holes on strong selenium donors in a neutral scaffold. Rational bite-angle adjustment to the long Se-C bonds was the key for BDS design. For the unprecedented BDS motif, synthesis of 12 analogs from o-xylene, crystal structure, σ hole variation strategies, optoelectronic properties, theoretical and experimental anion binding as well as catalytic activity are reported. Chloride binding increases with the depth of the σ holes down to K_D = 11 μM in THF. Catalytic activities follow the same trend and culminate in rate enhancements for transfer hydrogenation of quinolines beyond 100000.

Full text of DOI:10.1039/c7sc03866f

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Catalysis with chalcogen bonds: neutral
benzodiselenazole scaffolds with high-precision
selenium donors of variable strength†
Cite this: DOI: 10.1039/c7sc03866f
*
Sebastian Benz, Jiri Mareda, Celine Besnard, Naomi Sakai and Stefan Matile
´
The benzodiselenazoles (BDS) introduced in this report fulfill, for the first time, all the prerequisites for non-
covalent high-precision chalcogen-bonding catalysis in the focal point of conformationally immobilized s
holes on strong selenium donors in a neutral scaffold. Rational bite-angle adjustment to the long Se–C
bonds was the key for BDS design. For the unprecedented BDS motif, synthesis of 12 analogs from
Received 4th September 2017
Accepted 6th October 2017
o-xylene, crystal structure,
s hole variation strategies, optoelectronic properties, theoretical and
experimental anion binding as well as catalytic activity are reported. Chloride binding increases with the
depth of the s holes down to KD ¼ 11 mM in THF. Catalytic activities follow the same trend and
culminate in rate enhancements for transfer hydrogenation of quinolines beyond 100 000.
DOI: 10.1039/c7sc03866f
rsc.li/chemical-science
The integration of new interactions into functional systems is attractive to stabilize anionic transition states with high preci-
an objective of highest, most fundamental importance.1–7 It sion in the focal point of the two cofacial s holes (Fig. 1),8
expands our ability to create function and promises access to but they are limited to weak sulfur donors. Bis(2-
new properties. In organocatalysis, a renewed interest in the selanylbenzimidazolium)s, used in stoichiometric amounts,
integration of conventional interactions such as dispersion provide access to more powerful selenium donors but suffer
forces,3 ion pairing4 or cation–p interactions5 accounts for from lack of precision due to conformational exibility and
much recent progress in the eld. Catalysis with halogen
a dicationic scaffold that obscures contributions from
bonds2,6 and anion–p interactions,7 the unorthodox counter- chalcogen bonding and adds complications from counterions.9
parts of hydrogen bonds and cation–p interactions, have been To overcome these problems, we here introduce
introduced recently to catalysis. The youngest in this series,
chalcogen bonds at work in non-covalent catalysis have been
reported earlier this year.8,9
Chalcogen bonds originate from the s holes on electron-
decient sulfur, selenium, tellurium but not oxygen atoms.10
Produced by the anti-bonding s* orbitals, the two s holes locate
in plane with the two covalent bonds (Fig. 1). Their sideward,
somewhat hidden position has limited attention to solid state
engineering and intramolecular covalent conformational
control, also in covalent catalysis.1,10–12 The appearance of
intermolecular chalcogen bonds in non-covalent supramolec-
ular systems is relatively rare and recent. Leading examples
include macrocycles13 and rotaxanes,14 anion binding,14,15 anion
transport16 and mechanosensitive probes.17
This year's rst two examples for non-covalent catalysis with
chalcogen bonds focus on dithieno[3,2-b:20,30-d]-thiophenes
(DTTs)8 and bis(2-selanylbenzimidazolium)s.9 DTTs are
Department of Organic Chemistry, University of Geneva, Geneva, Switzerland; Web:
stefan.matile@unige.ch; http://www.unige.ch/sciences/chiorg/matile/; Tel: +41 22
379 6523
Fig. 1 The BDS (top, 1–12) and DTT motif (bottom, 13) with electron-
rich chalcogen-bond acceptors (red) bound in the focal point of the s
holes (blue), together with the semitransparent cutaway molecular
electrostatic potential (MEP) surface of 40 (R2 ¼ pMePh, MP2/6-
311++G**//M062X/6-311G**, isosurface: 0.008 au; red: ꢀ0.010 au,
blue: 0.096 au).22
† Electronic supplementary information (ESI) available: Detailed procedures and
results for all reported experiments. CCDC 1568432. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c7sc03866f
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benzodiselenazoles (BDS) as an unprecedented structural motif sulfur bridge in the hypothetical “DSeT” by a double-atom
that unies powerful selenium donors with high-precision carbon bridge in the BDS scaffold brought the bite angle back
chalcogen bonding in the focal point of conformationally to the desired 45ꢁ (Fig. 2d-B, black arrows; Fig. 2e*). In
immobilized s holes of variable strength (i.e. 1–12, Fig. 1).
computed BDS-chloride complexes of 10, the resulting bond
Bite or bent angle adjustment is of utmost importance in angles were correct, and the bond length as short as in DTTs
supramolecular systems.18 Determined by the orientation of the despite the large radius of selenium and the presence of sulde
antibonding s* orbital, Se–Cl chalcogen bonding, highly donors rather than sulfone acceptors (Fig. 2a vs. c).
directional, is strongest with a C–Se–Cl bond angle of 180ꢁ. For
Benzo[1,2-d:4,3-d0]di([1,3]selenazole)s have not been re-
chalcogen bonding in the focal point of the two donors in ported previously. However, similar structures have been
scaffolds derived from 2,20-biselenophene or -thiophene, the explored, mainly for materials applications,19 and BDS synthesis
ideal Cl–Se–Se or Cl–S–S bite angle is thus around 45ꢁ (Fig. 2*). could be extrapolated from the known benzoselenazoles.20 The
Smaller and larger angles move the focal point too close and too most active catalyst 4 was constructed from ortho-xylene 14
far away from the donors, respectively, resulting in a formal (Scheme 1). Bromination gave the tetrasubstituted benzene 15,
outward and inward bending of the chalcogen bonds, i.e., weak nitration the fully substituted benzene 16. Classical trans-
binding.
formations afforded diamine 17 by reduction, amide 18 with
DTTs such as 13 offer an ideal Cl–S–S bite angle of 45ꢁ for the formic anhydride, and isocyanate 19 by dehydration with
weaker sulfur donors (Fig. 2c**).8,16 As a result, chalcogen bonds phosphoryl chloride, all in good yield. Incorporation of sele-
to chloride ions are short and co-linear with the C–S bond. In nium gave isoselenocyanate 20. Loosely reminiscent of the
simple dithiophenes, bite angles are too small (34ꢁ), resulting in Edman degradation,21 the cyclization into the BDS tricycle 5 was
ꢁ
8,16
˚
longer bonds (3.4 A) with incorrect bond angles (149 ). The initiated by reacting isoselenocyanate 20 with p-tert-butyl-
single-atom sulfur bridge in DTTs caused the outward rotation phenyl (PTBP) thiol in the presence of NaH at 0 ꢁC. The
of the peripheral thiophenes that was needed to adjust the bite resulting selenothiocarbamate intermediate was treated with
angle.
Because of the length of the C–Se bond, a formal sulfur– cycles by triggering the formation of the Se–C bond.
selenium exchange from DTTs to “DSeTs” would increase the The acceptors on the C2 bridge were installed by bromina-
a catalytic amount of CuI and 1,10-phenanthroline to close the
bite angle to 53ꢁ (Fig. 2d-A, red arrow). This enlarged bite angle tion of BDS 5 with NBS and transformation of the obtained
would move the focal point away from the Se donors and thus dibromide 21 over diazide 22 into dicyanide 1. The crystal
either stretch or bend, i.e., weaken the chalcogen bond. To structure of BDS 1 conrmed the structure of this new motif and
readjust the bite angle, an inward rotation of the selenophenes provided with CHCl3 in the focal point of the s holes the rst
was required (Fig. 2d-B). The replacement of the single-atom indications of powerful chalcogen bonding (Fig. 3a). Finally, the
sulde donors in 1 were oxidized to sulfoxide and sulfone
acceptors.
Catalysts with octyl and adamantly substituents as R2 were
prepared analogously using the corresponding thiols for cycli-
zation (Fig. 1)22 to complete the catalyst collection 1–12. All
selenium-containing products showed the characteristic
isotope distribution in the mass (Fig. 3b) and signals in the 77Se
NMR spectra.22
Fig. 2 (a, b) DFT-M062X/6-311G** models of chloride (green) bound
to BDS 10 (R2 ¼ pMePh) in (a) anti and (b) syn conformation of PTBP Scheme 1 (a) Br2, I2, neat, rt, 10 h, 52%; (b) HNO3/H2SO4, rt, 8 h, quant;
sulfide substituents. (c) Same for DTT 130 (R2 ¼ Me). (d) Overlay of DTT (c) Fe, AcOH/EtOH, reflux, 1 h, 55%; (d) 1. HCOOH/Ac2O, 40 ꢁC, 1 h; 2.
(dashed, blue, c), “DSeT” (red, solid) and BDS (dotted, black, b) on their 17, 0 ꢁC to rt, 3 h, 57%; (e) Et3N, CH2Cl2, POCl3, rt, 4 h, 90%; (f) Se, Et3N,
C2 carbon (red circle). (A) Shift of chalcogen atom from DTT to “DSeT”. CHCl3, 90 ꢁC, 14 h, quant; (g) 1. NaH, PTBP-SH, THF, 0 ꢁC, 30 min, 66%;
(B) Change of bite angle from “DSeT” (53ꢁ) to BDS (*, 45ꢁ) by inward 2. CuI, 1,10-phenanthroline, Cs2CO3, DME, reflux, 2 h, 45%; (h) NBS,
rotation around C2. (e) Overlay of DTT (blue, c) and BDS (yellow, a) on AIBN, DCE, reflux, 2.5 h, 75%; (i) NaN3, THF/DMSO, rt, 14 h, quant; (j)
their chalcogen atom (blue circle).
DDQ, DCE, 150 ꢁC, mW, 1 h, 30%; (k) mCPBA, CH2Cl2, rt, 4 h, 45%.
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In computational models of 1, chloride binding with the
PTBP sulde substituents in syn conformation was preferred by
5.7 kcal molꢀ1 (Fig. 2b and Table 1, entry 3). The anti conformer
shows shorter chalcogen bonds with perfect bond angles
(Fig. 2a). However, the syn conformer contains additional, very
7
˚
weak (Cl–CPh $ 3.8 A) anion–p interactions to the p-basic
phenyls that move the chloride away from the focal point of the
s holes, thus elongating the chalcogen bonds and decreasing
the angles (Fig. 2b).
Contrary to the crystal structure of 1 with CHCl3 instead of
Clꢀ (Fig. 3a), the phenyl rings in the computed chloride
complex of 10 bend inward to catch the chloride anion in
a tweezer-like motion (Fig. 2b). The result is a nicely preor-
ganized, dynamic binding pocket with an attractive combina-
tion of (weak) anion–p interactions and (strong) chalcogen
bonds that reects the found strong anion binding very well. In
models with molecular electrostatic potential (MEP) surfaces,
catalyst 40 appeared like a molecular crab, with the mouth
represented by the s holes nicely visible on selenium donors
that look like eyes, and the phenyl substituents reminiscent of
the exible claws (Fig. 1).
In the anti conformer of disulfoxide 20, competition from
intramolecular chalcogen bonds to sulfoxide oxygens further
weakened anion binding (Fig. S8†). As a result, the preference to
the syn conformers increased to 10.9 kcal molꢀ1 for sulfoxide 20
(Table 1, entry 4). Inactivation by intramolecular chalcogen
bonds might contribute to the comparably small increase in
activity from suldes 1 to sulfoxides 2 (binding and catalysis,
below, Table 1, entries 3, 4).
Fig. 3 (a) Crystal structure of 1 with CHCl3. (b) Simulated (pink) and
measured ESI mass spectrum of 4 (blue). (c) Normalized absorption
spectra of 2, 3, 4, 1 and 5 in THF (increasing lmax). (d) Absorption
spectra of 2 in THF with increasing concentrations of TBACl (0 to
1.95 mM, blue to red). (e) Conversion h of 23a with 30 mol% 1 (>), 2
(,), 3 (B) and 4 (C) as a function of time, with trend lines.
The electron-rich BDS 5 absorbed at lmax ¼ 332 nm (Fig. 3c,
Table 1, entry 1). The cyano acceptors in 1 and sulfoxides in 2
gradually blue-shied this maximum down to lmax ¼ 295 nm.
Further oxidation to sulfones in 3 and 4 shied it back up to
lmax ¼ 300 nm. Cyclic voltammograms showed a semi-
reversible reduction wave (Fig. S6†) with LUMO energies
decreasing with withdrawing substituents down to ꢀ3.81 eV for
4 (Table 1, entry 6).
Chloride binding in THF was detectable by UV absorption
spectroscopy (Fig. 3d). The obtained KD's decreased with
increasing depth of the s holes down to an outstanding KD ¼ 11
ꢂ 2 mM for BDS 4 (Table 1, entry 6). They exceeded anion
recognition with the best comparable DTT 13 by two orders of
magnitude (KD ¼ 1130 ꢂ 30 mM) and corresponded well with
computed interaction energies Eint (Table 1).
Taken together, crystal structures (Fig. 3a), neutral, green
MEPs on the aromatic surface of the BDS (Fig. 1),23,24 LUMO
levels at ꢀ3.81 eV or higher (Table 1),23 and the structure of
minimized computational models of chloride complexes (Fig. 2,
S7 and S8†) rmly excluded signicant contributions from
anion–p interactions between anions and BDS. The same
crystal structure and minimized chloride complexes, and the
Table 1 Characteristics of benzodiselenazoles
c
e
g
h
DEa
Eint
d (%) (kcal molꢀ1
ELUMO
(eV)
lmax
3i
Entry Cpda R1a
na ma R2a
kcat/kuncat
(kJ molꢀ1
)
h
)
KD (mM)
(nm)
332
(mMꢀ1 cmꢀ1
)
b
f
1
2
3
4
5
6
7
8
9
10
5
6
1
2
3
4
7
8
9
13
CH3
CH3
CN
CN
CN
0
1
0
1
1
2
0
1
2
2
0
1
0
1
2
2
0
1
2
—
PTBP ꢃ10
—
n.d
93
n.d.
78
ꢀ25.7
ꢀ34.1
n.d.
n.d.
27.2
PTBP 660
PTBP 100
ꢀ15.8
ꢀ11.3
ꢀ37.2 (ꢀ31.5)j n.d.
ꢀ3.21
ꢀ3.54
ꢀ3.74
ꢀ3.81
307
295
298
300
79.1
62.5
69.5
60.3
PTBP 970 (500)k ꢀ16.8
ꢀ45.2 (ꢀ34.3)j 530 ꢂ 90
PTBP 3200
PTBP 150000
Ad
Ad
Ad
iBu
ꢀ19.6
ꢀ29.1
—
ꢀ19.6
ꢀ13.9
ꢀ15.3m
88
ꢀ49.2 (ꢀ38.0)j 37 ꢂ 6
CN
93l
n.d.
97
ꢀ53.0 (ꢀ41.6)j 11 ꢂ 2
CH3
CH3
CH3
CN
ꢃ10
3100
300
n.d.
n.d.
n.d.
47
490m
96m
ꢀ34.6m
1130 ꢂ 30m ꢀ3.70m 376m
18.3
a
b
Compounds, see Fig. 1; n, m: number of oxygens bound to sulfur, 0 ¼ sulde, 1 ¼ sulfoxide, 2 ¼ sulfone. Rate enhancement for product
formation from 23a (128 mM) and 24 (281 mM) in CD2Cl2 at 20 ꢁC with 30 mol% catalyst 1–13, compared to kuncat ¼ 3.9 ꢄ 10ꢀ5 Mꢀ1 hꢀ1
.
c
d
e
Change in activation energy, from kcat/kuncat
.
Yields determined by 1H NMR signal integration. Computed (M062X/6-311G**) chloride
binding energy (gas phase, entry 1–6: R2 ¼ pMePh). Dissociation constant for TBACl in THF. LUMO energy, in eV against ꢀ5.1 eV for Fc+/Fc.
f
g
h
l
i
j
k
Absorption maximum in THF. Extinction coefficient at lmax
. syn (anti) conformer. Data obtained for a chiral (and the meso) diastereomer.
Same yield with reduced catalyst loading of 1 mol%. m Data from ref. 8. n.d., not determined.22
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highly positive, deep blue MEP surface toward the focal point of of electron-rich systems (Table 1, entries 1, 7, Table S1†).
the s holes of the BDS (i.e., the mouth of the molecular crab, Oxidation of sulde donors to sulfoxide acceptors in 6, 8 and 11
Fig. 1) provided compelling support for operational chalcogen and sulfones in 9 and 12 gradually deepened the s holes and
bonding. Experimental and theoretical evidence for strength- turned on catalytic activity (Table S1†). Surprisingly high activ-
ened chloride binding by deepened s holes conrmed the val- ities found for BDS 8 with adamantyl substituents on the sulf-
idity of this conclusion. For instance, the weak sulde donors in oxide level did not extrapolate to further increases with sulfone
BDS 1 produced shallow s holes on the Se donors, which 9 (Table 1, entries 8, 9).
resulted in undetectable chloride binding in THF and
Replacement of the methyl donors by cyano acceptors in the
computed interaction energies for chloride complexes of C2 bridge to deepen the s holes on the Se donors produced
maximal Eint ¼ ꢀ37.2 kcal molꢀ1 (Table 1, entry 3). Sulfoxide detectable rate enhancements kcat/kuncat ¼ 100 already with
acceptors in BDS 2 produced deeper s holes, detectable chloride sulde BDS 1 (Table 1, entry 3). Upon replacement of the sulde
binding in THF with KD ¼ 530 ꢂ 90 mM and stronger Eint
¼
donors by chiral sulfoxide acceptors in BDS 2, activities
ꢀ45.2 kcal molꢀ1 in computed chloride complexes (Table 1, increased up to kcat/kuncat ¼ 970 as expected for stronger chal-
entry 4). One even stronger sulfone acceptor in BDS 3 further cogen bonding by deepened s holes on the Se donors (Fig. 3e,
deepened the s holes and increased chloride binding in THF to and Table 1, entry 4). Further rate enhancements up to kcat
/
KD ¼ 37 ꢂ 6 mM and in silico to Eint ¼ ꢀ49.2 kcal molꢀ1 (Table 1, kuncat ¼ 3200 upon adding one strong sulfone acceptor in BDS 3
entry 5). The deepest s holes of the series in BDS 4 with two were consistent with deepened s holes and strengthened
strong sulfone and two strong cyano acceptors, nally, coin- chloride binding in THF and in computed chloride complexes
cided with the strongest chloride binding in THF and in (Fig. 3eB and Table 1, entry 5). Finally, the highest rate
computed complexes (KD ¼ 11 ꢂ 2 mM, Eint ¼ ꢀ53.0 kcal molꢀ1
,
enhancement of more than a hundred thousand was achieved,
as expected, by BDS 4 with maximized s holes by two strong
Table 1, entry 6).
Evidence for efficient anion stabilization in the ground state sulfone and two strong cyano acceptors and is consistent with
implied that chalcogen bonding with BDS could also stabilize equally maximized chloride binding in solution and in silico
anionic transition states in the focal point of the s holes of their (Fig. 3eC and Table 1, entry 6). The best BDS catalyst 4 was thus
Se donors. Previous computational studies have indicated that more than two orders of magnitude more active than the best
neutral lone pairs extending from the endocyclic aromatic comparable DTT 13 (Table 1, entries 6, 10; DTT diimides: kcat
/
nitrogen in the substrate 23 are already well recognized even kuncat ¼ 1290).8 These consistent trends demonstrated that
with weak sulfur donors.8 This chalcogen bonding should transition-state stabilization by chalcogen bonds in the focal
increase with increasing negative charge accumulation on the point of neutral selenium donors of maximized strength
nitrogen atom, that is stabilize the transition states of the (Fig. 4b) exceeds that by equally activated but weaker sulfur
nucleophilic addition to nitrogen-containing aromatic hetero- donors by far.
cycles. For transfer hydrogenation of quinolines 23, the negative
The meso diastereomer of sulfoxide 2 was markedly less
charge injected by the hydride should be attracted to and, in the active than its chiral counterpart (Table 1, entry 4). This dia-
transition state, be located on the endocyclic nitrogen (Fig. 4b). stereoselectivity conrmed that the location of both PTBP
This would enable transition-state stabilization in the focal substituents on the same side of the aromatic plane (Fig. S8†)
point of the s holes of BDS, and hence could result in rate hinders chalcogen-bond activation of the substrate. The higher
enhancement of the transfer hydrogenation, i.e., catalysis with activity of the chiral diastereomer of sulfoxide 2 with the PTBP
chalcogen bonds.
substituents on opposite sides of the BDS plane (Fig. S8†) sug-
Without catalyst, the transfer hydrogenation of quinoline gested that the binding of the nitrogen lone pair in the focal
23a with Hantzsch ester 24 affords tetrahydroquinoline 25a and point of the chalcogen-bond donors can occur with an angle
pyridine 26 with kuncat ¼ 3.9 ꢄ 10ꢀ5 Mꢀ1 hꢀ1 (Fig. 4a).6,8 With between the quinoline and BDS planes that is <90ꢁ (Fig. 4). This
donating substituents, BDS such as 5, 7 and 10 were as inactive likely twist in a chiral environment was however insufficient for
as expected for poor chalcogen bonding to the shallow s holes asymmetric catalysis: enantiopure sulfoxide catalysts 2, isolated
by chiral HPLC, failed to produce signicant enantioselectivity
(not shown).
Having identied 4 as a potent chalcogen bonding catalyst,
catalyst loading was successfully reduced to 1 mol%, which
furnished the product 25a in identical yield of 93% aer 24 h
reaction time (Table 1, entry 6). Under these conditions, transfer
hydrogenation of a variety of substituted and unsubstituted
quinolines was explored (Table 2 and Fig. 4). Both electron-rich
(Table 2, entries 2, 8) and electron-poor quinolines (Table 2,
entries 1, 6) were smoothly reduced. Substrates with methoxy
donors were naturally less reactive (Table 2, entry 7). Substrates
with chloride and nitro acceptors were essentially not converted
(Table 2, entries 3, 4). This result suggested that the electron
density on the nitrogen is insufficient to bind to the s holes in
Fig. 4 (a) Transfer hydrogenation of quinolines 23a–h (R3–R5: Table 2)
with catalysts 1–13 and (b) the expected transition-state stabilization
by chalcogen bonding, exemplified for substrate 23a and catalyst 4.
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Table 2 Substrate screening
5 (a) C. R. Kennedy, S. Lin and E. N. Jacobsen, Angew. Chem.,
¨
Int. Ed., 2016, 55, 12596–12624; (b) T. M. Brauer, Q. Zhang
Entry
Sa
R3
R4
R5
tb (h)
hc (%)
and K. Tiefenbacher, Angew. Chem., Int. Ed., 2016, 55,
7698–7701.
6 A. Bruckmann, M. A. Pena and C. Bolm, Synlett, 2008, 6, 900–
902.
7 (a) Y. Zhao, Y. Domoto, E. Orentas, C. Beuchat, D. Emery,
J. Mareda, N. Sakai and S. Matile, Angew. Chem., Int. Ed.,
2013, 52, 9940–9943; (b) Y. Cotelle, V. Lebrun, N. Sakai,
T. R. Ward and S. Matile, ACS Cent. Sci., 2016, 2, 388–393.
1
2
3
4
5
6
7
8
23a
23b
23c
23d
23e
23f
Ph
H
Cl
H
Me
H
H
H
H
H
H
H
Br
H
H
H
H
H
NO2
F
H
OMe
Me
24
24
48
48
24
24
24
24
93
89 (98)d
0
9
80 (88)d
98
23g
23h
32 (58)d
97
H
´
8 S. Benz, J. Lopez-Andarias, J. Mareda, N. Sakai and S. Matile,
a
b
Substrates, see Fig. 4. Reaction time with 23a–h (128 mM), 24 (281
c
mM) and 1 mol% 4 in CD2Cl2 at 20 ꢁC. Yield of the reduced product,
Angew. Chem., Int. Ed., 2017, 56, 812–815.
9 P. Wonner, L. Vogel, M. Duser, L. Gomes, F. Kniep,
B. Mallick, D. B. Werz and S. M. Huber, Angew. Chem., Int.
Ed., 2017, 56, 12009–12012.
determined by 1H NMR signal integration against internal standard.
¨
d
Yields in brackets determined aer 48 h reaction time.
10 (a) B. R. Beno, K.-S. Yeung, M. D. Bartberger,
L. D. Pennington and N. A. Meanwell, J. Med. Chem., 2015,
the catalyst, and chalcogen bonding to the acceptors might be
preferred. Catalyst 4 was further conrmed to catalyze the imine
reduction in N-benzylidene-aniline with Hantzsch ester 24
(Scheme S6†). The amine product was obtained in quantitative
yield.
Compared to hydrogen-bonding catalysis, chalcogen-
bonding catalysis is expected to excel with unique direction-
ality, that is highest precision, particularly in hydrophobic
environments. In the new BDS scaffold, this directionality is
maximized. Synthesized from ortho-xylene, the best BDS binds
chloride with low micromolar KD's in THF and enhances the
rate of transfer hydrogenation by ve orders of magnitude.
Increasing activities with deepening s holes are consistent with
powerful chalcogen bonds at work (Table 1, clearest for entries
3–6) and encourage further development of the concept,
particularly with regard to asymmetric catalysis and the inte-
gration into more complex systems.6,16,17b,25
`
58, 4383–4438; (b) A. Bauza, T. J. Mooibroek and
A. Frontera, ChemPhysChem, 2015, 16, 2496–2517; (c)
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D. Romo, Angew. Chem., Int. Ed., 2010, 49, 9479–9483; (d)
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Conflicts of interest
There are no conicts of interest to declare.
¨
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Acknowledgements
We thank the NMR and the Mass Spectrometry platforms for
services, and the University of Geneva, the Swiss National
Centre of Competence in Research (NCCR) Molecular Systems
Engineering, the NCCR Chemical Biology and the Swiss NSF for
nancial support.
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