Chiral chalcogen bond donors based on the 4,4'-bipyridine scaffold

Article abstract of DOI:10.3390/molecules24244484

Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well as the catalytic activity evaluation of the 5,50-dibromo-2

Full text of DOI:10.3390/molecules24244484

molecules
Article
Chiral Chalcogen Bond Donors Based
on the 4,40-Bipyridine Scaffold
Robin Weiss 1, Emmanuel Aubert 2 , Paola Peluso 3,*, Sergio Cossu 4 , Patrick Pale 1
and Victor Mamane 1,
*
1
Strasbourg Institut of Chemistry, UMR CNRS 7177, Team LASYROC, 1 rue Blaise Pascal,
University of Strasbourg, 67008 Strasbourg CEDEX, France; robin.weiss@unistra.fr (R.W.);
ppale@unistra.fr (P.P.)
2
3
4
Crystallography, Magnetic Resonance and Modelisations (CRM2), UMR CNRS 7036, University of Lorraine,
Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France; emmanuel.aubert@univ-lorraine.fr
Institute of Biomolecular Chemistry ICB, CNR, Secondary branch of Sassari, Traversa La Crucca 3,
Regione Baldinca, 07100 Li Punti, Sassari, Italy
Department of Molecular Science and Nanosystems DSMN, Ca’ Foscari University of Venice, Via Torino 155,
30172 Mestre Venice, Italy; cossu@unive.it
*
Correspondence: paola.peluso@cnr.it (P.P.); vmamane@unistra.fr (V.M.); Tel.: +39-079-2841218 (P.P.);
+33-3-68851612 (V.M.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 7 November 2019; Accepted: 3 December 2019; Published: 6 December 2019
Abstract: Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle
was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well
as the catalytic activity evaluation of the 5,50-dibromo-2,20-dichloro-3-((perfluorophenyl)selanyl)-
4,40-bipyridine as organocatalyst. The latter is based on the use of two electron-withdrawing groups,
a pentafluorophenyl ring and a tetrahalo-4,40-bipyridine skeleton, as substituents at the selenium
center. Atropisomery of the tetrahalo-4,40-bipyridine motif provides a chiral environment to these new
ChB donors. Their synthesis was achieved through either selective lithium exchange and trapping or
a site-selective copper-mediated reaction. Pure enantiomers of the 3-selanyl-4,40-bipyridine were
obtained by high performance liquid chromatography enantioseparation on specific chiral stationary
phase, and their absolute configuration was assigned by comparison of the measured and calculated
electronic circular dichroism spectra. The capability of the selenium compound to participate in
σ
-hole-based interactions in solution was studied by 19F NMR. Even if no asymmetric induction has
been observed so far, the new selenium motif proved to be catalytically active in the reduction of
2-phenylquinoline by Hantzsch ester.
Keywords: atropisomerism; 4,40-bipyridine; chalcogen bond; electronic circular dichroism;
noncovalent interactions; organocatalysis; selenium; σ-hole
1. Introduction
The term chalcogen bond (ChB) describes the intermolecular interaction occurring between
a Lewis base (BL) and a group 16 atom (S, Se, Te) which behaves like Lewis acid, according to the
recommendations of the International Union of Pure and Applied Chemistry (IUPAC) (net attractive
interaction between an electrophilic region associated with a chalcogen atom in a molecular entity and
a nucleophilic region in another, or the same, molecular entity) [
-hole-based interactions [ ], among which the most prominent and most studied is halogen bonding
(XB) [ ]. ChB possesses many similarities with XB [ ], but with a different interaction pattern,
because up to two
-hole···BL axes can be identified on a Ch atom due to its divalent nature (Figure 1).
Although noncovalent contacts involving sulfur have been recognized in biological molecules during
1–3]. ChB belongs to the family of
σ
4
5–
7
8,9
σ
Molecules 2019, 24, 4484; doi:10.3390/molecules24244484
www.mdpi.com/journal/molecules

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the past decade [10], it is only recently that a few applications involving ChB in solid state [11
]
and in solution [12] have appeared, in particular those involving heavier elements such as selenium
and tellurium.
Figure 1. Halogen and chalcogen bonds (EWG: Electron withdrawing group, BL: Lewis base).
Among the applications based on
research area. While several catalysts acting as XB donor have been described during the last
decade [ 13 14], the first examples of ChB-based catalysis have been very recently reported by the
groups of Matile [15 18], Huber [19 21], and Wang [22]. Other recent applications of ChB concern
σ-hole interactions in solution, catalysis represents an active
6, ,
–
–
anion binding [23,24] and transport [25–27].
Introduction of chirality in systems able to interact through noncovalent bonds can have
a significant impact in many areas, including biology, molecular recognition, catalysis, and material
sciences [28
developed in the last few years [5,6, ,
,
29]. Unlike XB-based processes, for which a number of chiral donor molecules were
12 30], only very few applications using chiral ChB donors
have been reported. Beer’s group described a chiral selenium-containing receptor for enantiomeric
discrimination of dicarboxylates [24]. Following previous studies on XB-based high performance
liquid chromatography (HPLC) enantioseparations [31–36], our groups demonstrated that ChB
can participate in the recognition process underlying the enantioseparation of sulfur-containing
atropisomeric 4,40-bipyridine 1 on a cellulose-based chiral stationary phase [37].
On this basis, we report here our results on the synthesis of thio- and seleno-substituted
4,40-bipyridines as ChB donors and the evaluation of compounds
1
and
reduction of 2-phenylquinoline (Figure 2). For this purpose, an improved synthetic protocol for the
synthesis of compound was developed and applied to the preparation of derivative . Compounds
and were active as ChB donor catalysts in the reduction of 2-phenylquinoline, but without
enantioselectivity induction. Moreover, studying the behavior of and in the presence of chloride
ions by 19F NMR revealed that these compounds form σ-hole bonds in solution.
2 as organocatalysts in the
1
2
1
2
1
2
Figure 2. Chiral 3-chalcogeno-4,40-bipyridines considered in this work.

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2. Results
2.1. Synthesis
The thio-substituted 4,40-bipyridine
1
was prepared in 21% yield from the readily available
pentahalogeno-4,40-bipyridine
bis(pentafluorophenyl)disulfide
3
[
38] by selective iodine/lithium exchange and trapping with
, according to our own method [37]. The same conditions were used
, and starting from and the corresponding diselenides 5a
4
to prepare the selenium derivatives
2,
6
7
3
–c
(Scheme 1). Although the expected products could be observed by NMR in the reaction mixtures,
their purification proved to be very challenging, and the final products could only be isolated with,
respectively, 34, 20, and 51% yield through HPLC purification.
Scheme 1. Synthesis of bipyridine derivatives 1, 2, 6, and 7 through a lithiated intermediate.
These difficulties and the resulting modest yields led us to consider the use of a cross-coupling
reaction involving 4,40-bipyridine
3
as starting material. Indeed, we already succeeded in selective
Pd-catalyzed couplings on halogenated 4,40-bipyridines [38
,
39]. However, the introduction of
SC6F5 and SeC6F5 groups onto haloaromatics through a cross-coupling reaction is poorly described
in the literature. Yagupolskii and coworkers described their copper-mediated coupling with
several iodoaromatics [40], and later, Haupt and coworkers applied this methodology to the
polyfunctionalization of corannulene [41]. On these bases, we screened several conditions starting
from
3 (Table 1), focusing on selectivity, which obviously is a major issue considering the number of
potentially reactive carbon–halogen positions.
Table 1. Synthesis of 1 and 2 through copper-mediated cross-coupling reaction.
Entry
ArChChAr
n (eq.) T (◦C)
NMR Ratio 3/1/8 or 3/2
Yield (%)
1
2
3
4
5
6
7
8
9
1.3
1.3
1.3
0.5
0.8
1.0
2.0
4.0
0.5
1.3
1.3
80
(C6F5S)2 (4)
33/67/0
12/77/11
4/31/65
78/20/2
53/43/4
39/57/4
0/75/25
0/54/46
49/42/9
17/63/20
14/86
−
74 (1)
39 (8)
−
100
130
100
100
100
100
100
130
100
100
‘’
‘’
‘’
‘’
‘’
‘’
‘’
‘’
−
−
67 (1)
−
−
10a
11
‘’
(C6F5Se)2 (5a
)
81 (2)
a
The reagents were mixed together without preforming the copper complex.

Molecules 2019, 24, 4484
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Methodology optimization was performed by using disulfide
4
(entries 1–10) in order to find the
best conditions for the selective mono-functionalization. The reactive copper complex [CuSC6F5] was
in situ produced by mixing with two equivalents of copper as a powder in N-methyl-2-pyrrolidone
(NMP) at room temperature for 3 h. Bipyridine was then added and the mixture was heated for
4
3
16 h at a given temperature. We first evaluated the effect of the temperature on the reactivity and
◦
selectivity starting with 1.3 eq. of
4
(entries 1–3). At 80 C, the reaction was not complete and
a substantial amount of starting product was still present (entry 1). At 100 ◦C, the conversion was
higher but the over-coupling compound
on the more substituted and electron-poor pyridine ring (see Supplementary Information for NMR
details). Under these conditions, the expected thiobipyridine could, nevertheless, be isolated in
good yield (74%, entry 2). Increasing further the temperature (130 ◦C) induced more formation of
allowing its isolation with 39% yield (entry 3). While keeping the temperature at 100 ◦C, the amount
of was increased from 0.5 to 4.0 eq. (entries 4–8) in order to evaluate the effect of electrophile
concentration. With half equivalent of (i.e., 1 eq. of the active copper species), the conversion was
very low (entry 4). Slight improvement was obtained by increasing the amount of to 0.8 eq. (entry
5) and then to 1.0 eq. (entry 6). With 2.0 and 4.0 eq. (entries 7 and 8), the starting bipyridine was
completely consumed, but the amount of increased with the increasing amount of copper reagent.
No improvement was observed by increasing the temperature to 130 ◦C while reducing the amount
of to 0.5 equiv (entry 9). Rewardingly, with 2.0 eq., the crude reaction mixture was clean and
could thus be isolated with 67% yield (entry 7). Mixing all the components without preformation of
[CuSC6F5] led to a higher formation of (entry 10). Under conditions optimized for mono-coupling
(as in entry 2), the selenobipyridine was obtained with 81% yield, starting from diselenide 5a (entry
, was not observed at 100 ◦C and could not be
8 appeared due to the insertion of a second SC6F5 group
1
8,
4
4
4
3
8
4
1
8
2
11). The bis-coupling product of selenium, analog to
8
obtained at 130 ◦C because decomposition mostly occurred.
2.2. Analyses
2.2.1. HPLC Enantioseparation and Electronic Circular Dichroism (ECD)
The atropisomeric pairs of bipyridines
HPLC multimilligram enantioseparation under normal phase elution conditions. As we previously
reported [37], the enantiomers of compound (>99% ee) were recovered by using Chiralpak
IA (immobilized amylose tris(3,5-dimethylphenylcarbamate)) as chiral column. On the contrary,
the enantioseparations of compounds , and were performed on Chiralpak IC (immobilized
cellulose tris(3,5-dichlorophenylcarbamate)) (Table 2).
1, 2, 6, and 7 were obtained in good amounts by means of
1
2
,
6
7
Table 2. Optimized multimilligram enantioseparation of 4,40-bipyridines 2, 6, and 7 a.
Absolute Configuration (e.e.b %)
Recovered Amounts [mg] (Recovery%)
Bipyridine
Racemate [mg]
1st Eluted Peak
2nd Eluted Peak
1st Eluted Peak
2nd Eluted Peak
2
6
7
30.0
40.0
12.0
>99
>99
>99
98.8
95.0
95.1
10.6 (70.7)
7.4 (37.0)
5.1 (85.0)
13.0 (86.7)
18.0 (90.0)
5.9 (98.3)
a Mobile Phase: n-Hexane/2-propanol 90:10, flow rate 0.5 mL/min, T = 22 ◦C. b Enantiomeric excess (e.e.) determined
by chiral HPLC under the same conditions used for recoveries.
As we demonstrated, the absolute configurations of HPLC-separated enantiomers of polyhalogenated
4,40-bipyridines can be successfully determined by electronic circular dichroism (ECD) coupled with
time-dependent density functional theory (TD-DFT) calculations [37–39,42]. These techniques were therefore
applied to each enantiomer of , and 7. Recorded in ethanol, their ECD spectra showed the expected
1, 2, 6
opposite traces for the two atropisomers (Figure 3; for ECD spectra of
Supplementary Information).
6 and 7, see Figures S1 and S2 in

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Figure 3. Electronic circular dichroism (ECD) spectra of the enantiomers of bipyridines 1 and 2.
DFT calculations were run at the CAM-B3LYP-D3/6-311+G(d,p) level of theory to explore
the conformation distribution in bipyridines and (Figure 4; for details concerning and
see Figures S3 and S4 in Supplementary Information) focusing on the pentafluorophenyl group
orientation. For compounds , and , four stable conformations were found. They originate
1
2
6
7,
1
,
2
6
from the relative orientation of the pentaflurophenyl ring that can be in front (conformation A) of
the upper pyridine ring or away from it (conformation B) due to rotation around the C–Ch bond.
For each of the two conformations, two additional conformers are generated by the relative position
of the pentafluorophenyl ring, which can be close to the H (conformations A1 and B1) or to the Br
(conformations A2 and B2) of the upper pyridine ring.
Figure 4. The different conformations calculated for bipyridine 2.
The relative energies of all conformers were calculated in EtOH using a polarizable continuum
model (PCM), allowing for the determination of their relative population (Table 3). The zero value of
energy was ascribed to the more stable conformers, that is, Conf. A2 for
1 and Conf. A1 for 2. We can
notice that the distribution of conformers A1, A2, and B1 is different for the two bipyridines, whereas
Conf. B2 is negligible in both cases.
Table 3. Relative energies and populations of the different conformers of 1 and 2.
1
2
A1
A2
B1
B2
A1
A2
B1
B2
∆G (kJ/mol)
Pop. (%)
0.66
30
0
39
0.74
29
8.09
2
0
50
3.17
14
0.96
34
7.53
2
The relative population of each conformer, calculated as Boltzmann statistics at 298.15 K,
was taken into account in order to calculate the ECD spectra of (M) enantiomers of bipyridines

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1
,
2, 6, and
absolute configurations of the enantiomers (Figure 5; for compounds
see Figures S9–S14 in Supplementary Information). The agreement between experimental ECD of the
first eluted enantiomer and theoretical spectra of (M)- was good, taking into account the systematic
shift of the calculated spectra to shorter wavelengths (10–15 nm), as evidenced in previous studies
using the same DFT function [39]. In conclusion, for all bipyridines and , peak 1 corresponds to
the (M) enantiomer and peak 2 to the (P) enantiomer. It is worth noting that the (P) configuration for
peak 2 of compound was confirmed by X-Ray analysis (see Figure S15 in Supplementary Information).
7
. Comparison of calculated and experimental ECD spectra allowed determining the
6, 7, and complete details,
1
1,
2,
6
7
6
Figure 5. Comparison of measured and calculated ECD spectra for (M)-1 and (M)-2.
2.2.2. X-Ray Diffraction
Compounds and
racemic could be observed and collected. The X-Ray analysis revealed a single molecule in the
◦
2 are oily, but after some days in the refrigerator (4 C), some crystals of
1
2
asymmetric unit, with a conformation very close to the conformer B2 calculated by DFT (root mean
square deviation = 0.16Å) (Figure 6).
Figure 6. ORTEP plot of 2 with ellipsoids drawn at the 50% probability level.
The structure of
2 displays various intermolecular interactions. Indeed, molecules are interacting
about the inversion center through π···π stacking (centroid–centroid distance of 3.7611(9) Å and
slippage of 1.293 Å) and cyclic C4–H4···N2 hydrogen bond (H4···N2 = 2.74Å; C4–H4···N2 = 156◦)
(Figure S16 in Supplementary Information). A type II halogen···halogen bond is observed where

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the
σ
-hole of Cl2(1 − x,y,z) is pointing toward the negative crown of Cl1(x,y,z) (Cl2···Cl1 = 3.349Å;
C9–Cl2···Cl1 = 177.14◦; Cl2···Cl1–C3 = 101.13◦) (Figure S17 in Supplementary Information). The
π-hole
of the pentafluoro ring is in interaction with the electron rich zone of atoms from three neighboring
molecules (N2 = (x,1/2 − y,1/2 + z), N1 = (1 + x,y,z) and the negative crown of Br1 = (1
−
x,1
−
y,1
−
z))
(Figure S18 in Supplementary Information).
2.2.3. 19F NMR Spectroscopic Titration with Tetrabutylammonium Chloride (TBACl)
With the aim to probe ChB, binding strength and pattern of bipyridines
1 and 2 with chloride
ions were studied in CD2Cl2 by 19F NMR. In addition, to give access to the corresponding binding
constants (Ka), this method is expected to give information on the possible competition between the
sulfur/selenium σ-holes and the C6F5 π-hole as electrophilic sites toward chloride
The structures of
interact with chloride ions through their
Cl/Br with -hole acceptors [37], we applied the method of Jin and co-workers [43] in order to identify
1
and
2
contain several atoms (Cl, Br, S/Se) or a group of atoms (C6F5) able to
σ
- or -hole. Assuming a preferential interaction of S/Se over
π
σ
the major interaction (S/Se σ-hole vs C6F5 π-hole) in compounds 1 and 2. These authors investigated
the
σ
-hole···Cl− (XB) vs.
π
-hole···Cl− competition by 19F NMR titration of C6F5X (X = F, Cl, Br, I) in the
presence of chloride anion. They observed a direct correlation between ∆δ of C6F5 upon addition of
Cl− and the site of interaction. Thus, with C6F6 and ClC6F5, which are prone to form
π-hole interaction
with Cl−, the fluorine chemical shifts (δF) moved to lower field. In contrast, with BrC6F5 and IC6F5,
which preferentially form a XB, δF moved to higher field.
The changes in the 19F NMR chemical shift (∆δ) of the ChC6F5 group were measured by incremental
addition of TBACl (from 1 to 200 eq.; see Supplementary Information for details) to a 0.006 mol.L−1
solution of
1 and 2 in CD2Cl2. As shown in Figure 7, δF of C6F5 (para-F) in 1 and 2 move to a higher
field with the increase in Cl−. The variation trends of ortho- and meta-F were lower in both compounds,
as previously reported [43]. These results show that both bipyridines 1 and 2 interact preferentially
with Cl− through the σ-hole of S and Se, respectively.
Figure 7. 19F NMR traces of bipyridines 1 (left) and 2 (right) upon addition of TBACl.
For the calculations of Ka, the measured shifts were plotted against the guest equivalents and
the resulting curves were fitted using the website calculator http://supramolecular.org/ (Figure 8
and Supplementary Information for details) [44]. By assuming a 1:1 binding model, Ka values
of 0.4 M−1 and 38 M−1 were obtained for compounds
that the Ka value for 2 (38 M−1
bis(pentafluorophenyl)selenium [17].
1
and
2, respectively. It is worth noting
)
is similar to the one obtained by Matile and coworkers with

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Figure 8. Chemical shift change (∆δ) of para-F in bipyridines 1 and 2 upon addition of TBACl.
2.3. Catalysis
The hydrogen-transfer reaction using Hantzsch ester (HE) as hydrogen source is a mild method
to reduce quinolines and other C=N substrates [45]. Brønsted acids are known to be particularly good
catalysts to promote this reaction [46]. In 2008, Bolm showed that haloperfluoroalkanes can be used as
XB catalysts for the reduction of 2-phenylquinoline 10 using HE [47]. Since then, this reduction has
often been used as a benchmark reaction to evaluate the activity of XB [48,49] and ChB [15,16] catalysts.
We therefore selected the reduction of 2-phenylquinoline 10 as a model substrate for investigating
1
the catalytic ability of the ChB donors
1
and
2
(Table 4). The reaction was followed by H NMR
over time and it was stopped after 72 h, even if complete conversion was not reached. The resulting
tetrahydroquinoline 11 was only isolated and the yield given, when the reaction was completed.
Table 4. Effect of ChB donors
1 and 2 and reference compounds on the catalytic reduction of 10 by HE.
Conv. (%)a
Yield (%)
Entry
Cat.
x (mol%)
Time (h)
1
2
3
4
5
1
2
1
2
2
-
2
12
13
3
20
20
5
5
5
-
5
20
20
20
20
20
48
48
72
72
18
72
18
72
72
48
72
48
100
100
81
100
54
0
38
62
78
68
100
100
87
94
−
88
−
6
−
7b
8
−
−
9
10
11
−
−
3
86
12
(P)-2
90 (0% ee)
a
b
Calculated by 1H NMR with hexamethylbenzene as internal standard. 1 eq. of TBACl was added.
Without catalyst, no conversion was observed after 72 h (entry 6). Rewardingly, with 20 mol% of
or 2 as catalysts, the reaction was complete after 48 h, delivering the fully reduced compound 11
1

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with 87% and 94% yields, respectively (entries 1 and 2). Interestingly, with only 5 mol% of
1, a good
conversion of 81% was still obtained after 72 h of reaction (entry 3). Under the same conditions,
catalyst was even more active, giving full conversion after 72 h, and compound 11 was obtained
2
with an isolated yield of 88% (entry 4). It is interesting to note that with
conversion only after 18 h (entry 5).
2, the reaction reached 54%
In the presence of 1 eq. of TBACl, the conversion was lower but not null (entry 7), showing that
probably the -hole of bromine atoms and/or the -hole of the C6F5 group took the relay in the catalytic
activation of the quinoline substrate. In order to verify this hypothesis, compounds 12 38] and 13 37
were tested as catalysts in the reaction (entries 8 and 9). Even with 20 mol%, the reaction did not
reach completion after 72 h, showing that the Se atom in compound is the primary site of interaction
σ
π
[
[
]
2
with the substrate. However, the 62% conversion obtained with 12 is an indication that bromine
atoms alone can activate the substrate (entry 8). The presence of the C6F5 group in 13 compared to 12
slightly increased the conversion from 62 to 78%, a result which revealed the modest contribution of
the
π-hole in the substrate activation (entry 9). With the iodinated compound 3, complete conversion
was reached only after 72 h, showing the beneficial effect of the SeC6F5 group compared to iodine
atom (entries 10 and 11). Finally, the (P) enantiomer of
2 was employed as catalyst, but unfortunately,
no asymmetric induction was observed (entry 12).
3. Discussion
The new motif, which 1 and 2 are based on, was designed by introducing on the Ch site two electron
withdrawing groups (EWGs), namely, a pentafluorophenyl ring and a tetrahalo-4,40-bipyridine scaffold.
Indeed, computation of electrostatic potential (EP) maxima on the Ch site indicates that fluorination
increase
(Figure 4, A1-type) structures of 5,50-dibromo-2,20-dichloro-3-chalcogeno-4,40-bipyridines
was determined by evaluating the EP maxima on calculated EP surfaces (DFT/B3LYP/6-311G*), proving
that EP maxima values on the Ch -hole increase upon fluorination (max EPCh: SePh ( ) < SC6F5 ( ) <
SeC6F5 ( )) (Figure 9 and Table 5). As expected, -hole depth increases with the polarizability of the Ch
atom. Moreover, the pentafluorophenyl moiety is a well-known -hole center [51]. On the other hand,
σ
-hole depth [50]. In our study, the ChB donor ability ranking for conformationally related
6
,
1, and
2
σ
6
1
2
σ
π
the tetrahalo-4,40-bipyridine skeleton contributes to increase the electrophilic character of the Ch atom
and makes the new motif chiral, due to its atropisomeric geometry. In contrast, most reported ChB
donors are characterized by a charged heterocyclic structure, which provides sufficient polarization to
the Ch atom [2,3,14]. Another peculiarity of the new motif described here is the possibility of rotation
around the C–Ch bond, which offers conformational adjustments/tuning during catalysis. It is worth
noticing that establishing strong ChBs requires angles R-Ch···BL close to 180◦, and thus, conformational
flexibility of the ChB donor catalyst should increase its catalytic efficiency. In this regard, it is worth
noting that, in the compounds so far studied as organocatalysts, the Ch sites are located in a rigid
heteroaromatic structure [15–21].
Figure 9. Ab initio electrostatic potential surfaces (EPS) of bipyridines 6, 1, and 2.

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Table 5. Electrostatic potential (EP) maxima [kJ/mol] on Ch σ-holes for compounds 1, 2, and 6 a.
σ-hole b
6
1
2
1
2
88.0
73.6
113.2
98.6
136.7
127.5
a
Spartan ’10 Version 1.1.0 (Wavefunction Inc., Irvine, CA), isovalue 0.002. b σ-hole (1) is located on the elongation of
the C–Ch bond; σ-hole (2) is located on the elongation of the CArF–Ch bond.
On this basis, sulfur- and selenium-based chiral catalysts
1
and
2
were prepared by two different
. The first method, based
methods from chiral 5,50-dibromo-2,20-dichloro-3-iodo-4,40-bipyridine
3
on a iodine–lithium exchange followed by quenching with bis(pentafluorophenyl)dichalcogenide,
delivered the expected products with low yields. Higher yields were obtained by a copper-mediated
coupling of pentafluorophenylthiolate and selenolate with 3. This method proved to be very efficient
and selective for the iodinated position. It is therefore expected to proceed with comparable efficiency
with other chiral polyhalogenated 4,40-bipyridines [42] and could represent a new entry to various
chiral chalcogen compounds.
The enantiomers of 1 and 2 were separated by HPLC on chiral stationary phase and their absolute
configuration was assigned by comparison of the measured and calculated ECD spectra. ECD analysis
showed that 5,50-dibromo-2,20-dichloro-3-(perfluorophenyl)chalcogeno- 4,40-bipyridines are present
in solution as a mixture of four conformers because of the rotation of the pentafluorophenyl group
along the C–Ch bond. Unfortunately, our efforts to detect these conformers in solution by variable
temperature 1H NMR were unsuccessful. We could, however, isolate few crystals of the selenium
derivative
2 (as a racemate) at low temperature and their XR structure only showed the presence of the
minor conformer B2, as revealed from the calculations in solution (Figure 4).
The ability of the chalcogen compounds to drive σ-hole-based interactions in solution was studied
through 19F NMR by incremental addition of chloride ions serving as strong acceptors. We observed
that δF of ChC6F5 move to a higher field with increasing chloride concentration, showing that both
bipyridines interact preferentially with Cl− through the
σ-hole of S and Se. Moreover, this study
allowed obtaining the binding constants values (Ka) of the 1:1 adducts between compounds
chloride ion.
1 or 2 and
After having shown that derivatives
activity was evaluated in the reduction of 2-phenylquinoline 10. As expected from the Ka values,
the Se compound was more active than its S analog . Therefore, the study was mainly focused on
the use of in comparison with reference compounds where the SeC6F5 group was replaced by CH3
12), CH2C6F5 (13), and I ( ). The reference compound 12 without a - or -hole donor in 3-position
was chosen so as to keep the torsional angle between the two pyridine rings similar to compound
in order to conserve the same geometry and to analyze only the effect due to the presence of the
SeC6F5 group. In agreement with the study in solution, the catalysis results show that interacts in
1 and 2 can behave as ChB donors in solution, their catalytic
2
1
2
(
3
σ
π
2
2
priority through the Se atom with the substrate. It is worth noting that other sites can interact with
the substrate, although to a lesser extent: The two bromine atoms in 5,50-position and the C6F5 group.
The last aspect concerns the absence of enantioselectivity when using enantiomerically pure (P)-2
.
This result may be due to the complex mechanism of the selected reaction (Scheme 2).

Molecules 2019, 24, 4484
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Scheme 2. Possible mechanism for the ChB-catalyzed reduction of 2-phenylquinoline 10.
After protonation of quinoline 10 by Hantzsch ester (HE), the first reduction occurs to give enamine
intermediate A. The latter is protonated to and then further reduced by the second equivalent of HE.
B
Both reductions can be activated by the ChB donor catalyst. A recent DFT study by Wang et al. with
a XB donor catalyst showed that in both reductions, the halogen atom interacts with the deprotonated
HE, thus facilitating the hydride transfer [52]. If the same activation mode occurs with catalyst (P)-2
through ChB, the chiral bipyridine backbone would be placed far from the C=N bond of the substrate,
and such spatial arrangement could explain the lack of asymmetric induction.
On these bases, we are currently working on the synthesis of analogs of 2, where bromines are
exchanged by chlorines or fluorines and the C6F5 group by a CF3. Furthermore, the search for new
ChB-catalyzed reactions, for which asymmetric induction could be achieved, are currently underway
in our laboratory.
4. Materials and Methods
4.1. General Information
Proton (1H NMR), carbon (13C NMR), fluorine (19F NMR), and selenium (77Se NMR) nuclear
magnetic resonance spectra were recorded on a Bruker Avance III instrument operating at 300, 400,
or 500 MHz (Bruker Corporation, Billerica, MA, USA). The chemical shifts are given in parts per
1
million (ppm) on the delta scale. The solvent peak was used as reference values for H NMR
(CDCl3 = 7.26 ppm) and for 13C NMR (CDCl3 = 77.16 ppm). An external standard was used for
19F NMR (trifluoromethylbenzene) and for 77Se NMR (diphenyl diselenide). Data are presented as
follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet
,
m = multiplet, b = broad), integration, and coupling constants (J/Hz). High-resolution mass spectra
(HRMS) data were recorded on a micrOTOF spectrometer (Bruker Corporation, Billerica, MA, USA)
equipped with an orthogonal electrospray interface (ESI). Analytical thin layer chromatography
(TLC plates from Merck KGaA, Darmstadt, Germany) was carried out on silica gel 60 F254 plates
with visualization by ultraviolet light. Reagents and solvents were purified using standard means.
Tetrahydrofuran (THF) was distilled from sodium metal/benzophenone and stored under an argon
atmosphere. Anhydrous reactions were carried out in flame-dried glassware and under an argon
atmosphere. Bipyridine 3 [38] and bis(perfluorophenyl)diselenide 5a [53] were prepared according
to the literature. All other chemicals were used as received. An Agilent Technologies (Waldbronn,
Germany) 1100 Series HPLC system (high-pressure binary gradient system equipped with a diode-array
detector operating at multiple wavelengths (220, 254, 280 nm), a programmable autosampler with

Molecules 2019, 24, 4484
12 of 16
a 20 µL loop, and a thermostated column compartment) was employed for multimilligram separations.
Data acquisition and analyses were carried out with Agilent Technologies ChemStation Version
B.04.03 chromatographic data software. The UV absorbance is reported as milliabsorbance units
(mAU). Chiralpak IA (immobilized amylose tris-3,5-dimethylphenylcarbamate) and Chiralpak IC
(immobilized cellulose tris-3,5-dichlorophenylcarbamate) were used as chiral columns (250
×
4.6 mm)
(5 m) (Chiral Technologies Europe, Illkirch, France). HPLC-grade n-hexane (Hex) and 2-propanol
µ
(IPA) were purchased and used as received. CD spectra were recorded on a « J-810 » from Jasco (JASCO
International Co. Ltd., Tokyo, Japan) at room temperature using 0.15–0.30 mM samples in ethanol
and a 1 mm quartz cell, with the following conditions: 100 nm/min scanning speed, 1 nm data pitch,
4.0 nm bandwidth, 1 s response time.
4.2. General Procedure for the Synthesis of 2, 6, and 7 from Bipyridine 3
Bipyridine
3
(0.19–0.47 mmol) was dissolved in THF (5–8 mL) and the solution was cooled to −78 ◦C
.
n-BuLi (1.2 M in hexanes, 1.01 eq.) was added dropwise and the mixture was stirred at
78 ◦C for 1 h.
−
A solution of diselenide 5a
78 ◦C for 30 min. The temperature was raised to room temperature during 5 h before addition of water
(10 mL). The mixture was extracted with ethyl acetate (4 10 mL); the organic phases were combined,
washed with brine (30 mL), and dried over anhydrous Na2SO4. After concentration, the crude was
purified by chromatography on silica gel (20% dichloromethane/pentane) and, if necessary, a flash
column chromatography was used to remove impurities (2% ethylacetate/cyclohexane).
–c (2.5 eq.) in THF (2–5 mL) was slowly added and stirring was maintained at
−
×
5,50-Dibromo-2,20-dichloro-3-((perfluorophenyl)selanyl)-4,40-bipyridine (
= 0.48 (40% dichloromethane/pentane). 1H NMR (500 MHz, CD2Cl2)
7.07 (s, 1H). 13C NMR (126 MHz, CD2Cl2)
155.1; 152.7; 152.6; 152.6; 151.2; 149.7; 148.6–145.8 (m);
144.1–141.2 (m); 139.5–136.8 (m); 126.1, 125.1 (d, J = 1.3 Hz); 120.3; 119.9; 102.6 (t, J = 23.3 Hz). 19F
127.1 (m); 150.7 to 150.8 (m); 159.8 to
160.0 (m). 77Se NMR
285.2. HRMS (ESI–TOF) [M + H]+ m/z: Calcd. for C16H4Br2Cl2F5N2Se 626.7198,
2). Colorless oil (46 mg, 34%). Rf
δ
8.66 (s, 1H); 8.62 (s, 1H);
δ
NMR (471 MHz, CD2Cl2) δ −127.0 to
−
−
−
−
−
(114 MHz, CD2Cl2)
found: 626.7180.
δ
5,50-Dibromo-2,20-dichloro-3-(phenylselanyl)-4,40-bipyridine (
6
). Colorless oil (54 mg, 20%). Rf = 0.29 (5%
1
ethylacetate/cyclohexane). H NMR (500 MHz, CDCl3)
δ 8.62 (s, 1H); 8.54 (s, 1H); 7.31–7.26 (m, 1H);
7.21 (t, J = 7.6 Hz, 2H); 7.17–7.12 (m, 2H); 6.71 (s, 1H). 13C NMR (126 MHz, CDCl3)
δ 155.5; 152.7; 152.0;
151.4; 150.3; 149.5; 132.8; 129.9; 129.7; 129.0; 128.6; 125.1; 119.7; 119.2.77Se NMR (114 MHz, CDCl3)
δ
425.2. HRMS (ESI–TOF) [M + H]+ m/z: Calcd. for C16H8Br2Cl2N2Se 536.7669, found: 536.7645.
5,50-Dibromo-2,20-dichloro-3-(methylselanyl)-4,40-bipyridine (
7
). Colorless oil (48 mg, 51%). Rf = 0.56 (5%
8.65 (s, 1H), 8.59 (s, 1H); 7.13 (s, 1H); 2.31 (s,
155.9; 152.8; 152.0; 150.9; 150.9; 150.5; 128.2; 124.6; 119.2; 118.6; 10.0.
δ
459.0. HRMS (ESI-TOF) [M + H]+ m/z: Calcd. for C11H7Br2Cl2N2Se
1
ethylacetate/cyclohexane). H NMR (500 MHz, CD2Cl2)
3H). 13C NMR (126 MHz, CD2Cl2)
δ
δ
77Se NMR (114 MHz, CDCl3)
474.7513, found: 474.7487.
4.3. General Procedure for the Copper-Mediated Synthesis of 1, 2, and 8
Under argon atmosphere, a 25 mL Schlenck tube was filled with copper powder (2 eq.) and
anhydrous NMP (1–3 mL). Bis(pentafluorophenyl)dichalcogenide (1.3 eq.) was added and the mixture
stirred for 3 h at room temperature. Bipyridine
overnight at a given temperature (100 or 130 ◦C). The reaction was allowed to cool to room temperature,
diluted with diethyl ether (30 mL), and filtered. The filtrate was washed with brine (4 15 mL).
3 (1 eq.) was added and the mixture was stirred
×
The organic phase was dried over Na2SO4, evaporated and the residue was submitted to two successive
columns chromatography on silica gel (5% diethyl ether/pentane for the first one and 2% diethyl
ether/pentane for the second).

Molecules 2019, 24, 4484
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Bipyridine 1 [37] was obtained as a colorless oil (85 mg; 74%) by using the following conditions (Table 1,
entry 2): Cu powder (24.8 mg, 0.39 mmol), bis(pentafluorophenyl)disuldife 4 (103.5 mg, 0.26 mmol),
bipyridine 3 (100.3 mg, 0.197 mmol), at 100 ◦C.
Bipyridine 2 was obtained as a colorless oil (245 mg; 81%) by using the following conditions (Table 1,
entry 11): Cu powder (63.5 mg, 1.0 mmol), bis(pentafluorophenyl)diselenide 5a (251 mg, 0.51 mmol),
bipyridine 3 (200.5 mg, 0.394 mmol), at 100 ◦C.
50-Bromo-2,20-dichloro-3,5-bis((perfluorophenyl)thio)-4,40-bipyridine (
as a colorless oil (16 mg, 39%) by using the following conditions: Cu powder (9.5 mg, 0.15 mmol),
bis(pentafluorophenyl) disuldife (30.6 mg, 0.077 mmol), bipyridine
(30 mg, 0.059 mmol), at 130 ◦C.
1H NMR (500 MHz, CDCl3) 8.59 (s, 1H); 8.47 (s, 1H); 7.12 (s, 1H). 13C NMR (125 MHz, CDCl3)
155.2;
8) (Table 1, entry 3). It was obtained
4
3
δ
δ
152.4; 152.2; 151.8; 151.0; 148.4–147.5 (m); 146.6; 146.4–144.9 (m); 140.08–135.52 (m); 128.6; 127.0, 124.6;
119.8; 106.9–105.4 (m); 106.8–105.6 (m). 19F NMR (471 MHz, CDCl3) δ −131.1 to
−
131.3 (m);
159.0 to
−
132.3 to
159.4 (m).
−
132.4 (m);
−
148.1 (t, J = 20.9 Hz);
−
150.0 (t, J = 20.8 Hz);
−
158.4 to
−
158.7 (m);
−
−
HRMS (EI+) [M]+ m/z: Calcd. for C22H3BrCl2N2S2 698.8257, found: 698.8211.
4.4. General Procedure for the Catalytic Reduction of 2-Phenylquinoline 10
2-Phenylquinoline 10 (9.5 mg, 49
µmol), Hantzsch ester (27.1 mg, 107 µmol) and hexamethylbenzene as
internal standard ( 2.23 ppm, s, 18H), were weighted in to a screw cap vial and suspended in dry degassed
δ
CD2Cl2 (1 mL). Then, the desired amount of catalyst (5 or 20 mol%) was added from a stock solution of catalyst
(120 mM). The vial was tightly sealed and stirred at 25 ◦C. 1H NMR spectra of aliquots of the reaction mixture
(5–10 µL) diluted in CDCl3 (0.5 mL) were recorded at varying time intervals. When the reaction was finished or
at 72 h maximum, the solvent was removed under reduced pressure and the remaining product was purified
by flash column chromatography on silica gel (3% ethyl acetate/pentane) to afford tetrahydroquinoline 11.
4.5. Crystal Data for 2
C16H3Br2Cl2F5N2Se, M = 627.88, monoclinic, a = 10.9949(5) Å, b = 13.7036(6) Å, c = 12.1716(6) Å,
V = 1827.20(15) Å3, T = 120(2) K, space group P21/c, Z = 4,
µ (Mo Kα
) = 6.775 mm−1, 74843 reflections
measured, 6383 independent reflections (Rint = 0.0467). The final R1 value were 0.0221 (I > 2
σ
(I)) and
0.0240 (all data). The final wR(F2) values were 0.0552 (I > 2
σ(I)) and 0.0560 (all data). The goodness of
fit on F2 was 1.117. CCDC no. 1963859.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/24/4484/s1:
Figures S1 and S2: ECD spectra of and ; Figures S3 and S4: Calculated conformations for and Figures S5–S8:
Comparison of measured and calculated UV spectra; Figures S9–S12: Calculated ECD spectra for each conformer
of (M)-1 (M)-2 (M)-6 and (M)-7; Figures S13 and S14: Comparison of measured and calculated ECD spectra for
(M)-6 and (M)-7; Figure S15: ORTEP plot of (P)-6; Tables S1–S5: X-Ray details for bipyridine Figures S16–S18:
, DFT details; Table S6: Anion binding experiments:
6
7
6
7;
,
,
2;
Intermolecular interactions in the X-Ray structure of
Overview of host addition; Table S7: Binding constants Ka for 1 and 2; Figures S19–S34: NMR spectra.
2
Author Contributions: Conceptualization, V.M. and P.P. (Paola Peluso); methodology, V.M. and R.W.; chemical
experiments, R.W.; HPLC, P.P. (Paola Peluso); D.F.T. calculations, E.A. and P.P. (Paola Peluso); X-ray analysis,
E.A.; inspiration and discussions, all authors; data curation, V.M.; writing—original draft preparation, V.M.;
writing—review and editing, R.W., E.A., P.P. (Paola Peluso), S.C., P.P. (Patrick Pale) and V.M.; funding acquisition,
V.M. and S.C.
Funding: This research was funded by the International Center Frontier Research in Chemistry (icFRC), the LabEx
CSC (ANR-10-LABX-0026 CSC), and Ca’ Foscari University of Venice, Italy (Department of Molecular Science and
Nanosystems, DSMN ADIR funds).
Acknowledgments: The authors thank the University of Strasbourg and the C.N.R.S. for their support.
The CINES/CEA CCRT/IDRIS is thanked for allocation of computing time (project A0030807449). High performance
computing resources were partially provided by the EXPLOR center hosted by the University of Lorraine.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2019, 24, 4484
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Sample Availability: Samples of the compounds 1, 2, 6 and 7 are available from the authors.
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