Synthesis and Characterisation of Chiral Triazole-Based Halogen-Bond Donors: Halogen Bonds in the Solid State and in Solution

Article abstract of DOI:10.1002/chem.201700618

A general platform for the synthesis of various chiral halogen-bond (XB) donors based on the triazole core and the characterisation of factors that influence the strength of the halogen bond in the solid state and in solution are reported. The characterisation of XB donors in the solid state by X-ray crystallography and in solution by ¹H NMR titration can be used to aid the design of new XB donors. We describe the first example of a XB between iodotriazoles and thioureas in solution. In addition, the enantiodiscrimination of acceptors in solution through halogen-bond participation is described.

Full text of DOI:10.1002/chem.201700618

A Journal of
Accepted Article
Title: Synthesis and characterization of chiral triazole-based halogen
bond donors: halogen bonds in solid state and in solution
Authors: Mikk Kaasik, Sandra Kaabel, Kadri Kriis, Ivar Järving, Riina
Aav, Kari Rissanen, and Tõnis Kanger
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To be cited as: Chem. Eur. J. 10.1002/chem.201700618
Link to VoR: http://dx.doi.org/10.1002/chem.201700618
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Synthesis and characterization of chiral triazole-based halogen
bond donors: halogen bonds in solid state and in solution
Mikk Kaasik,[a] Sandra Kaabel,[a] Kadri Kriis,[a] Ivar Järving,[a] Riina Aav,[a] Kari Rissanen,[b] and Tõnis
Kanger*[a]
papers concerning XB catalysis is still quite limited. Bolm et al
were the first to use XB catalysis in a quinoline reduction with
Hantzsch ester.[9] Since then several other articles have been
published,[10,11,12] mainly by Huber. However, to the best of our
knowledge, there are no examples of asymmetric XB catalysis.
To move towards that, information how different XB donor or
acceptor entities and their substituents influence the strength of
halogen bonds is needed. For example, a too weak XB donor
might not be sufficiently Lewis acidic to form a XB with the
acceptor, while a too strong XB donor may bind irreversibly to
the acceptor. Therefore it is essential that the strength of the XB
follows the “goldilocks” principle.[13]
Abstract: A general platform for the synthesis of various chiral
halogen bond (XB) donors and characterization of factors that
influence the strength of the halogen bond in the solid state and in
solution is presented. The XB donors are based on the triazole core.
The characterization of XB donors in the solid state by X-ray
1
crystallography and in solution by H NMR titration can be used to
aid the design of new XB donors. We describe the first example of a
XB between iodotriazoles and thioureas in solution. In addition, the
enantiodiscrimination of acceptors in solution via halogen bond
participation is described.
The halogen substituted 1,2,3-triazole core is a central
motif among XB donors.[14] Despite this, only one example of the
halotriazole based XB-catalysis has been published.[11g] These
compounds can be synthesized in one step through a click
reaction from readily available substrates.[15,16] Various chiral
azides, different halides or differently substituted aromatics can
be used which means that the structural variations of the
obtained XB donors is very broad. This opens wide opportunities
for further studies on the application of halotriazoles as XB
Introduction
A halogen bond (XB) is a noncovalent interaction between an
electrophilic halogen atom and some nucleophilic counterpart of
the same or another molecule.[1] The governing feature of the
XB is its directionality, primarily as the result of the anisotropic
distribution of electron density on the polarized halogen atom,
leading to the formation of the electron-deficient region called
the σ-hole.[ 2 ] As the σ-hole of the halogen atom is located
exactly on the elongation of the covalent bond the halogen atom
is involved in, the XB is almost linear.[3] Another feature of the
XB is its strength tunability, which is dependent on the nature of
the interacting counterparts. In general, the XB donor ability of a
halogen can be tuned by subtle structural modifications affecting
the electron withdrawing ability of moieties covalently bound to
that halogen atom or the steric environment surrounding the
halogen atom. In addition, the XB donor strength follows the
polarizability order F < Cl < Br < I[4] while the most commonly
used acceptor atoms can be ranked in the order O < S < N.[5]
These phenomena have been widely exploited in crystal
engineering to construct supramolecular complexes and
networks.[ 6 ] The application of the XB in solutions is more
challenging.[ 7 ] The most exciting application is using XB in
organocatalysis. Similarities between the XB and the hydrogen
bond make XB donors potential organocatalysts. While
hydrogen bonding catalysis is well-documented[8, the number of
catalysts. Because of this,
a family of halotriazoles was
synthesized and their XB donor abilities were assessed by X-ray
crystallography and solution NMR studies. Acceptors containing
a sulphur or a nitrogen atom were chosen for solution studies as
the propensity of the sp2-hybridized sulphur[17] and imines[11c,f] to
form XB is known. These acceptors could also be considered as
model compounds of possible substrates in organocatalytic
applications. It is also noteworthy that although a sulphur atom is
a common acceptor in the solid state, only a few examples have
been reported regarding its use as an XB acceptor in solution
and those mainly deal with molecular iodine as the donor.[16d-f]
Finally, enantiodiscrimination capability of the iodotriazolium
salts towards chiral thiourea was addressed.
Results and Discussion
A library of triazole and triazolium XB donors with a different
substitution pattern was synthesized via a cycloaddition reaction
as a key transformation. The obtained triazoles differ from each
other in term of the main entities that determine the XB donor
ability of a compound. Triazoles 3a-c (Scheme 1) and the
corresponding triazolium salts 4a-c (Scheme 2) contain different
halogen atoms (iodine, bromine and chlorine, respectively). Two,
one or no trifluoromethyl substituents in the aromatic ring
(compounds 3a, 3d, 3e and corresponding salts) have clearly
different electronegativities influencing the XB donor
abilities.[5b,18] The influence of trifluoromethanesulfonic (triflate)
and tetrafluoroborate counterions (4a and 5a) on XB strength
can also be compared. All synthesized XB donors were chiral,
[a]
Mr Mikk Kaasik, Ms Sandra Kaabel, Dr. Kadri Kriis, Dr. Ivar Järving,
Dr. Riina Aav, and Prof. Dr. T. Kanger*
Department of Chemistry and Biotechnology
Tallinn University of Technology
Akadeemia tee 15, 12618 Tallinn, Estonia
E-mail: tonis.kanger@ttu.ee
Acad. Prof. Dr Kari Rissanen
University of Jyvaskula, Department of Chemistry
Nanoscience Center
[b]
P.O. Box 35, FI-40014 Jyvaskyla, Finland
Supporting information for this article is given via a link at the end of the
document.
1
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10.1002/chem.201700618
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enabling the investigation of the enantioselective recognition of
acceptors. [14a] Donors with two halogen atoms (3h-j, 5h and 4j)
could act by bidentate coordination with acceptors (Scheme
3).[14d,19]
Y
N
X
N
X
X - I, Br, Cl
Y - OTf, BF4
*Q - substituent
containing
stereocenter
MeOTf or Me3OBF4
N
N
N
N
Ar
Ar
*Q
*Q
CH2Cl2
50 - 92%
3 (a-g)
4 (a-g) Y = CF3SO3
5a Y = BF4
a) for 3a, 3d-g:
CuI, TBTA or TTTA
MeCN or THF
Ligand:
TBTA
N
Scheme 2. Quaternization of triazoles 3a-g.
N
N
N
Bn
N
N
N
N
Ar
3
N
X
*Q-N3
+
Ar
or
*Q
C2-symmetric bidentate XB donors 3h[11g] and 3i were
derived from aromatic diiododiyne 6 (Scheme 3). For the
synthesis of the non-symmetrically substituted bidentate donor
3j equimolar amounts of benzyl azide and alkaloid-based azide
were reacted with diyne 6. In addition, 3h was converted to bis-
tetrafluoroborate salt 5h and 3j was converted to the
corresponding tetrakis triflate salt 4j.
N
N
X
3
b) for 3b:
CuBr, Cu(OAc)2,
THF
2
1
TTTA
Et3N
3
CF3
CF3
CF3
CF3
CF3
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
CF3
I
Br
Cl
3c
: 79%
3a
3b
: 76%
Ph
: 71%
N
N
I
N
N
N
N
2
BF4
CF3
Ph
N
N
N
N
N
Me3OBF4
CH2Cl2
N
N
I
N
N
N
N
N
I
I
I
I
3e
3d
: 84%
: 96%
Ph
Ph
CF3
Ph
Ph
N
CF3
3h
74%
5h
81%
N
N
N
A)
N
I
N
N
N3
TTTA, CuI,
THF
Ph
O
O
CF3
I
Ph
CF3
OMe
B)
N
I
I
N
N
N
N3
N
N
3g
3f: 65%
: 80%
N
N
N
N
I
I
O
6
N
Scheme 1. Synthesis of monodentate XB donors.
N
O
O
N
Et3N, CuI, THF
C)
3i 60%
N
XB donors were synthesized via a click reaction between
N3
Ph
N3
enantiomerically pure azide
1
and iodoalkyne[16a] or
1 equiv.
O
bromoalkyne[16b] 2 affording halo-substituted triazoles 3 in good
Et3N, CuI,
THF
N
1 equiv.
to excellent yields (Scheme 1). Chiral azides were derived from
4
OTf
(R)-α-methylbenzylamine
phenylglycine (for 3f) or quinidine (for 3g). In addition, the
aromatic substituents 3,5-ditrifluoromethylphenyl, 4-
(for
compounds
3a-e,
(R)-
N
N
N
N
N
N
N
N
N
N
N
N
N
N
I
I
I
I
Bn
Bn
trifluoromethylphenyl or phenyl were varied in the alkyne starting
compounds 2. In most cases tris[(1-benzyl-1H-1,2,3-triazol-4-
MeOTf
CH2Cl2
O
O
N
N
yl)methyl]amine
(TBTA)
or
tris((1-tert-butyl-1H-1,2,3-
4j
3j 33%
63%
triazolyl)methyl)amine (TTTA) was used as a ligand in the click
reaction (3a, 3d-3f), alternatively Et3N was used in some cases
(3g) (Scheme 1). Bromine derivative 3b was obtained via a
CuBr/Cu(OAc)2 catalysed click reaction in THF (Scheme 1, b).
The XB donor containing a chlorine atom in the triazole ring (3c)
was synthesized from the iodotriazole 3a through the halogen
exchange reaction. [20]
The quaternization of the nitrogen atom can be used to
make the triazole core even more electron-deficient, polarising
the C-X bond and enlarging the σ-hole (Scheme 2). [14d,18] The
quaternization of the triazole ring was carried out using methyl
triflate or trimethyloxonium tetrafluoroborate affording triflate
salts (4a-g) or tetrafluoroborate salt (5a) in reasonable to good
yields (Scheme 2, experimental details are described in
Supporting Information). In the case of compound 3g the
reaction was not selective, affording the tris-triflate salt 4g, which
was insoluble in chloroform. The methylation of the nitrogen
atoms of the quinuclidine and quinoline ring can be avoided by
protecting them as N-oxides.[21] Regrettably, this strategy did not
yield the desired product.
Scheme 3. Synthesis of bidentate XB donors.
The first evidence of the XB donor properties of
synthesized compounds was obtained via single crystal X-ray
crystallography in the solid state. The presence of halogen
bonds can be determined by the reduction of the sum of van der
Waals radii between the interacting atoms. The strength of a XB
between different atoms can be found by using the normalized
interaction ratio RDA = dDA/(DvdW + AvdW), where dDA (in Å) is the
distance between the donor (D) atom and the acceptor atom (A)
divided by the sum of the van der Waals radii (in Å) of D and A.
In the case of a XB it is defined as RXB and the XB can be
considered to be strong if RXB < 0.9.[3, 22 ] Quantitative data
obtained from single crystal X-ray diffractions are presented in
Table 1 and are illustrated in Figures 1-3 (CCDC 1522079-
1522089 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
2
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Figure 2. X-ray structure of 3i. Atomic displacement ellipsoids are drawn at
30% probability level, solvent molecules are omitted from the figure and only
the quinoline fragments of the two 3i acceptor units are displayed for clarity.
The acceptor fragments are drawn as sticks.
Cambridge
www.ccdc.cam.ac.uk/data_request/cif).
Crystallographic
Data
Centre
via
A
B
Cationic XB donors (Table 1, entries 5-11) formed halogen
bonds with their counterions (Figure 3). Changing the halogen
atom in the triazole core from iodine to bromine or chlorine had a
profound effect on the strength of the XB (Table 1, entries 5-7),
to the extent that 4c did not form an XB with the triflate anion.
This is in agreement with previous studies showing the
importance of the polarizability and electronegativity of the
halogen atom on the strength of the XB.[2,4] Electron-withdrawing
trifluoromethyl groups in the phenyl ring of 4a and 4d (Table 1,
entries 5, 8) had little effect on the XB strength. Electron-
withdrawing methyl ester group at the N-substituent of the
triazole core in compound 4f did not affect the strenght of XB
(Table 1, entries 5, 9). Similarily to neutral XB donors, the salt
4g, containing the bulky quinidine substituent, formed the
strongest XB in the series of cationic XB donors. Finally, based
Figure 1.
X-ray structures of 3a (A) and 3g (B). The atomic displacement
ellipsoids are drawn at a 50% probability level.
The synthesized compounds can be divided into two
groups: neutral triazoles and triazolium salts. They are clearly
differentiated from each other by the type of atoms halogen
bonded in the crystalline state. The XB was, in the case of
neutral donors, formed between the iodine atom and a nitrogen
atom of another donor (Table 1, entries 1-4). Compound 3a
forms the XB with the nitrogen atom of the triazole core (Figure
1, A); while 3g with the nitrogen atom of the quinoline fragment
(Figure 1, B). In order to exclusively evaluate the influence of
substituents of the triazole ring on the XB strength (expressed
as RXB) only X-ray structures, where the XB was formed to the
same acceptor entity can be directly compared, as the strength
of the bond depends both on the donor and the acceptor.
Accordingly, it was determined that the XB between 3g and 3g
is stronger than one between 3a and 3a, as the nitrogen of the
quinoline fragment is a better acceptor than the nitrogen of the
electron-deficient triazole fragment (Table 1, entries 1, 3).
Furthermore, it is assumed that the electronegative
trifluoromethyl groups on the phenyl ring of compound 3a
decrease the acceptor ability of the triazole nitrogen to a greater
extent than increase the donor ability of the iodine. This
assumption was supported by the fact that the XB between 3e
and 3e was stronger than one between 3a and 3a (Table 1,
entries 1, 2). Steric effects seemed to have little influence on the
strength of the XB (Figure 2), as 3i with two bulky quinoline
fragments formed two comparably strong C−I···Nquinoline halogen
bonds similary to 3g, which had only one quinoline unit (Table 1,
entries 3, 4).
Table 1. Solid-state bond parameters for XB donor compounds
[b]
Entry
XB
donor
XB
system
Angle C-
X … A / °[a]
Distance
RXB
X… A / Å[a]
1
3a
3e
3g
3i
C – I … Ntriazole
167.4(2)
167.1(2)
168.8(1)
171.4(3)
168.9(4)
163.6(2)
-
2.940(5)
2.854(6)
2.749(3)
2.785(8)
2.82(1)
2.870(6)
-
0.833
0.808
0.779
0.789
0.807
0.852
-
2
C – I … Ntriazole
3
C – I … Nquinoline
C – I … Nquinoline
C – I … OSO2CF3
C – Br … OSO2CF3
4
5
4a
4b
4c
4d
4f
6
7
C – Cl …
-
8
C – I … OSO2CF3
C – I … OSO2CF3
C – I … OSO2CF3
C – I … FBF3
166.5(1)
166.1(5)
172.7(2)
158.7(2)
2.847(3)
2.83(1)
2.715(3)
2.890(3)
0.813
0.809
0.776
0.838
9
10
11
4g
5a
[a] Standard deviations given in parentheses. [b] Sum of van der Waals
radii calculated based on the values defined by Bondi.[23]
on the X-ray data the oxygen of the triflate counterion was a
better XB acceptor than the fluorine of the tetrafluoroborate
counterion (Table 1, entries 5, 11).
3
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the HypNMR2008 program (Figure 5, B).[24]. Due to solubility
issues in CDCl3 compounds 4g, 4j and 5h were not used,
although multidentate XB donors have shown higher binding
affinities.[19a,f]
B
A
A
a
c
b
39 eq.
26 eq.
16 eq.
12 eq.
8.1 eq.
6.3 eq.
4.3 eq.
3.1 eq.
2.2 eq.
1.7 eq.
1.5 eq.
1.3 eq.
1.1 eq.
0.8 eq.
0.6 eq.
0.4 eq.
0.2 eq.
0 eq.
Figure 3.
X-ray structures of 4g (A) and 5a (B). Only one OTf-counterion, the
one involved in XB bonding is included in the figure of 4g, the rest are omitted
for clarity. Atomic displacement ellipsoids are drawn at 50% probability level.
Overall, the observed XBs were not noticeably stronger in
the case of cationic XB donors compared to neutral donors. The
increase in XB donor strength by quaternization was penalized
by the presence of a weaker XB acceptor, as an oxygen atom
(moreover in a weakly coordinating triflate anion) is a weaker
acceptor than a nitrogen atom. As the strength of the XB relies
on the interplay of multiple simultaneous effects, then pin-
pointing the effect of a single substituent needs to be addressed
cautiously. Nonetheless, the observed XBs were relatively
strong as all of them have RXB values less than 0.86. In all cases
the XB adopted a near-linear geometry, with the greatest
distortion of the XB from linearity in crystals of compounds 4b
and 5a, which also formed the weakest halogen bonds (Table 1,
entries 6, 11).
4.36 4.30 4.24
3.54 3.48 3.42 3.36 3.30
f1 (ppm)
B
a
CF3
CF3
0
OTf
N
N
N
d
d
δ
δ
(a) of 4a
(b) of 4a
Ph
I
-0,02
b
4a
S
c
δ
N
N
-0,04
H
H
7
-0,06
CF3
CF3
OTf
N
N
N
0
0,02
[7] / M-1
0,04
The strength of the XB in the solid state cannot be directly
extrapolated to solution. The involved compounds are fixed in
the crystal structure into one preferable conformation by the
packing forces, whereas in solution XB formation can be
influenced by steric effects created by the conformational
freedom of the molecule. In addition, solvent effects in solution
must be accounted for, as interactions between the solvent
molecule and donor/acceptor will also interfere with XB
formation.
Ph
H
4k
Figure 5. A) Outtake of 1H NMR spectra (CDCl3, 297 K, 400 MHz) from the
titration experiment of 4a (1.5 m ) with thiourea 7 showing the methyl protons
a and b of 4a and the methylene protons c of 7. From 1 to 18 increasing
equivalents of 7. B) The corresponding binding isotherm with global fitting of
methyl protons a and b; Ka = 42 ± 2.
M
S
S
O
N
N
N
N
N
N
N
First, the influence of the halogen atom on the formation of
XB with thiourea 7 in solution was studied. As expected the
binding constant for the iodine containing complex [4a–7] was
the largest of the three (Table 2, entries 1-3). Surprisingly, the
chlorine containing triazole 4c gave a higher binding constant
with 7 than the bromine containing donor 4b (Table 2, entry 2
and entry 3). It is assumed that hydrogen bonding between the
acidic N-H protons of the thiourea 7 and the electron-rich
equatorial belt of the halogen atom were able to assist in XB
formation.[2,25] To eliminate the influence of hydrogen bonding
via acidic N-H protons on the titration results N,N,N’,N’-
tetramethylthiourea 8 was used in the experiment with donors
4a–4c (Table 2, entries 9-11). The binding constant for the
complex [4a–8] was lower than for the complex [4a–7], also the
complex formation between triazoliums salts 4b or 4c and
thiourea 8 is not favoured. This confirmed the participation of the
hydrogen bond in the formation of a complex with 7. A chlorine
atom is more electronegative and less polarizable compared to a
bromine or an iodine atom. Because of this the the σ-hole of the
chlorine atom is generally weaker than the σ-hole of the iodine
H
H
7
10
8
9
CF3
CF3
S
S
N
MeO
N
N
CF3
N
N
CF3
H
H
H
H
N
N
11
(S,S)-12
(R,R)-12
Figure 4. XB acceptors used in this study.
To confirm the XB donor strength of the synthesized
compounds in solution a series of H NMR titration experiments
1
were carried out in CDCl3.[5b,d,14,19c-f,22a] During the titration
experiments the concentration of the XB donor was kept
constant while increasing amounts of acceptor (Figure 4) were
added to the solution. The upfield shifts of methyl protons a and
b of the XB donor were monitored during the titration experiment
(Figure 5, A) and used to calculate the binding constants for a
1:1 binding model by non-linear least square global fitting using
4
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or bromine atom and therefore hydrogen bonding was the major
contributor to the relatively large binding constant of the [4c–7]
complex. On the other hand, a bromine atom is a weaker XB
donor than iodine and also a weaker hydrogen bond acceptor
than chlorine, therefore the binding constant for the [4b–7]
complex was the smallest of the three (Table 2, entries 1-3). To
get additional evidence of XB in solution compound 4k (Figure
5) containing a hydrogen atom instead of a halogen atom was
synthesized by click reaction followed by subsequent
quaternization with methyl triflate. During the titration of 4k with
thiourea 7, the resonance frequencies of the methyl protons a
and b did not change indicating the absence of an interaction
(Table 2, entry 7). This showed the structural importance of the
iodine atom in 4a and that 4a acted as a XB donor in solution.
compounds 4f and 7 (Table 2, entry 6). In the solid state the RXB
values for 4a and 4f were practically identical (Table 1, entries 5
and 9). Therefore, it was assumed that additionally to the XB
also hydrogen bonding between hydrogens of thiourea 7 and the
ester functionality of 4f contribute to the observable binding
constant. To eliminate the possibility of hydrogen bond formation,
4f was titrated with tetramethylthiourea 8 (Table 2, entry 12). A
significantly smaller binding constant for the [4f–8] complex
compared to the binding constant for the [4f–7] complex
confirmed the presence of additional hydrogen bonding in the
case of the latter. Nevertheless the ester functionality had some
effect on the XB strength as the binding constant for the [4f–8]
complex is slightly larger than that for the [4a–8] complex (Table
2, entries 9, 12). Counterion effects in halogen bonding are as of
yet not fully understood and might not be as simple as using a
less coordinating counterion to enhance the XB strength.[Error!
Bookmark not defined.a,Error! Bookmark not defined.d]
-1) of XB complexes in CDCl3 at 297 K.
The binding constant for
Table 2. Binding constants Ka
(
M
[4a–7] complex was lower than for the [5a–7] complex (Table 2,
entries 1 and 8), presumably because the triflate counterion
interacts more strongly with the iodine of the triazolium
compared to tetrafluoroborate counterion (based on X-ray data,
Table 1, entries 5 and 11).
[a]
Entry
1
XB donor
4a
XB acceptor
Ka
7
42 ± 2
11 ± 1
29 ± 6[b]
35 ± 2
33 ± 1
129 ± 12[c]
-
2
4b
7
Donor 4a was additionally used in titration experiments
with urea 9. The exchange of a sulphur atom for an oxygen atom
brought about a twofold decrease of the binding constant (Table
2, entries 9, 13). This again indicates that thiocarbonyl
compounds could be better suited over carbonyl compounds as
substrates in organocatalytic applications of halogen bonding.
Finally 4a was used in titration experiments with imine 10 and 11
(Table 2, entries 14, 15). Unfortunately, no significant interaction
was detected between 4a and 10. Introducing an electron
donating methoxy group to the aromatic ring of imine 10 made it
possible to measure the binding constant for the [4a–11]
complex (Table 2, entry 11). Although the constant was quite
small it was still larger than previously reported binding
3
4c
7
4
4d
7
5
4e
7
6
4f
7
7
4k
7
8
5a
7
58 ± 1
12 ± 1
0.10 ± 0.02[d]
0.05 ± 0.02[d]
20 ± 4[c]
6 ± 1
9
4a
8
10
11
12
13
14
15
4b
8
c]
constants for halogen bonds to imines.[Error! Bookmark not defined.
4c
8
So far only a handful of studies have addressed the issue
of enantiodiscrimination through XB. Beer et al described
enantioselective recognition of chiral anions of BINOL-based XB
donors.[14a] A separation based on XB of polyhalogenated 4,4’-
bipyridines by HPLC was investigated by Peluso.[26] To evaluate
the enantiodiscrimination properties of the synthesized donors,
NMR spectra of chiral acceptors (R,R)-12 and (S,S)-12 in 1:1
mixtures with chiral donor 4a were studied (Figure 6). Upon the
addition of (R,R)-12 or (S,S)-12 to 4a a complex was formed,
which is evident in the noticeable upfield shifts of the methyl
protons a (-0.021 or -0.023 ppm) and b (-0.019 or -0.035 ppm)
of 4a and the downfield shifts of methine protons k (0.027 or
0.035 ppm) and N-methyl protons l (0.043 ppm) of (R,R)-12 and
(S,S)-12. A different change in chemical shifts was expected as
formed complexes were diastereomeric.
4f
8
4a
9
4a
10
11
-
4a
8 ± 1[c]
[a] Global fitting based on the shift change of methyl protons a and b, with the
corresponding fitting errors. [b] Fitting based on the shift change of methyl
protons b. [c] Fitting based on the shift change of methyl protons a. [d]
Titration experiment carried out with 15 mM concentration of donor 4.
Lowering the electron-withdrawing power of the aromatic
substituent had little effect on the binding constant as the
constants for the [4d–7] and [4e–7] complexes are identical and
only slightly smaller than the binding constant for the [4a–7]
complex (Table 2, entries 1, 4, 5). The position of the
trifluoromethyl group in the aromatic ring must also be
considered, because it affects the triazole core only through
induction. The NMR results taken together with X-ray results
indicate that trifluoromethyl groups and their substitution pattern
should be suitable for the final fine-tuning of the halotriazole XB
donor. The largest binding constant was measured between
5
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a
OTf
values an upfield shift (in ppm) compared to the corresponding resonance
signals in either the spectrum of free 4k or (S,S)-12.
CF3
CF3
k
N
N
S
N
Ph
N
N
CF3
H
H
CF3
I
N
b
l
(
-12
4a
S,S)
Conclusions
l
k
Various chiral halotriazole and halotriazolium XB donors that
differ from each other in terms of the main entities that define the
XB donor properties have been synthesized. We have shown
that the general approach for the characterization of XB donors
(
)-12
S,S
-0.019
-0.035
-0.021
0.043
0.043
0.027
0.035
4a + (R,R)-12
4a + (S,S)-12
4a
1
-0.023
in the solid state by X-ray crystallography and in solution by H
NMR titration can be used to aid the design of new XB donors.
Structural modifications influence the XB strength to a varying
degree and can thus be grouped in two. The choice of halogen
used in the donor was crucial for the XB formation, also the
strength of the XB was effected considerably by the choice of
the counterion. On the other hand, trifluoromethyl groups on the
phenyl substituent had little impact on the XB strength.
Substituents that have a weak influence on the XB donor ability
are also important for the fine-tuning of a XB catalyst and thus
trifluoromethyl groups should be suited for this purpose. We
described the first example of XB between iodotriazoles and
neutral acceptors in solution (thioureas 7, 8, 12, urea 9 and
imine 11). Among the acceptors, thioureas formed XBs more
preferably, especially if there was the possibility of additional
hydrogen bond formation. Finally, evidence that the synthesized
compounds are capable of enantiodiscrimination in solution was
obtained. Thus, we have provided a platform for the synthesis
and characterization of chiral XB donors. Our ongoing
investigations are focused on the applications of the synthesized
donors in the field of asymmetric organocatalysis.
a
b
8.98 7.86
7.80 4.34
4.28 2.40 2.36 2.32 2.
f1 (ppm)
Figure 6. From 1 to 4 outtakes of 1H NMR spectra in CDCl3 (1.5 m
M
, 297 K,
400 MHz): 1) 4a, 2) 1:1 mixture of 4a and (S,S)-12, 3) 1:1 mixture of 4a and
R,R)-12, 4) (S,S)-12. Positive values indicate a downfield shift and negative
(
values an upfield shift (in ppm) compared to the corresponding resonance
signals in either the spectrum of free 4a or (S,S)-12.
To confirm that the observed changes in chemical shifts of
4a and enantiomers of 12 were caused by XB, the interaction
with compound 4k, where the possibility of the formation of the
complex via XB was excluded, was examined (Figure 7). When
4k was used in 1:1 mixtures with (R,R)-12 or (S,S)-12 there was
little change in the chemical shifts of interest. More importantly
the spectra corresponding to the 1:1 mixtures were practically
identical indicating that two diastereoisomeric complexes were
not formed. Thus, it can be concluded that the complexation of
donor 4a and thiourea 12 takes place via XB participation and
the donor 4a can differentiate between enantiomeric ureas 11
via chiral recognition. To the best of our knowledge, this is the
first example of the enantiodiscrimination of neutral acceptors by
XB participation.
CF3
a
CF3
CF3
OTf
k
N
N
N
S
Ph
N
N
CF3
H
H
H
N
b
k
l
(
-12
S,S)
4k
l
(S,S)-12
0.004
4k + (R,R)-12
-0.001
-0.001
-0.001
-0.001
-0.001
-0.001
0.005
4k + (S,S)-12
4k
a
b
7.84
7.78
4.30
4.24 2.38 2.34 2.30 2.
f1 (ppm)
Figure 7. From 1 to 4 outtakes of 1H NMR spectra in CDCl3 (1.5 m
400 MHz): 1) 4k, 2) 1:1 mixture of 4k and (S,S)-12, 3) 1:1 mixture of 4k and
R,R)-12, 4) (S,S)-12. Positive values indicate a downfield shift and negative
M, 297 K,
(
6
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(KBr tablet): ν = 3097 (w), 1618 (w), 1520 (w), 1458 (w), 1137 (s), 899
(m), 700 (m) cm-1; HRMS (ESI): m/z calcd for C18H13F6IN3 [M + H]+:
512.0053; found: 512.0048.
Experimental Section
General Information: All commercially available reagents were used
without further purification. CH2Cl2 was dried by distillation over P2O5,
MeOH over sodium metal. All air or moisture sensitive reactions were
carried out under argon atmosphere using oven-dried glassware. The
reactions were monitored by thin layer chromatography (TLC) with silica
gel-coated aluminum plates (Merck 60 F254) and visualized with KMnO4,
anisaldehyde or ninhydrine stain. Yields refer to chromatographically
purified or crystalized products. 1H NMR spectra were recorded at 400
MHz and are reported in parts per million (δ) referenced to the residual
solvent signal (CDCl3 δ = 7.26, MeOD δ = 3.31 ppm). Data for 1H NMR
spectra are as follows: chemical shift δ (ppm), multiplicity (s = singlet, bs
= broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of
doublets, m = multiplet), coupling constant J [Hz], and relative integration.
13C NMR spectra were recorded at 101 MHz and are reported in parts
per million (δ) referenced to the residual solvent signal (CDCl3 δ = 77.16,
MeOD δ = 49.00 ppm). HRMS spectra were recorded with an Agilent
Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer by
using AJ-ESI ionization. MS spectra were measured on a Shimadzu
GSMS-QP2010 spectrometer on a 70 eV EI. Optical rotations were
obtained with an Anton Paar GWB Polarimeter MCP500. IR spectra were
recorded on a Bruker Tensor 27 FT infrared spectrophotometer. Infrared
absorption frequencies in wavenumbers are listed, with the relative
strength in parentheses (w = weak, m = medium, s = strong, br = broad).
Synthesis of other triazoles is described in the Supporting Information.
Synthesis of triazolium salts:
(R)-4-(3,5-bis(trifluoromethyl)phenyl)-5-iodo-3-methyl-1-(1-
phenylethyl)-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate (4a)
Trizole 3a (0.090 g, 0.176 mmol) was dissolved in CH2Cl2 (3.5 mL) under
argon atmosphere. Methyl triflate (0.030 mL, 0.264 mmol) was added
dropwise and the reaction mixture was stirred at r.t. for 3 days. Et2O (5.0
mL) was added to the reaction mixture and fine precipitate formed which
was filtered to provide trifluorosulfonic salt 4a as colourless crystals
25
(0.101 g, 85% yield). M.p. 185–189 °C; [α D
]
= 33.9 (c = 0.21 in
methanol); 1H NMR (400 MHz, [D4]methanol) δ 8.38 (bs, 1H), 8.33 (bs,
2H), 7.54 – 7.40 (m, 5H), 6.27 (q, J = 6.9 Hz, 1H), 4.33 (s, 3H), 2.14 (d, J
= 6.9 Hz, 3H); 13C NMR (101 MHz, [D4]methanol) δ 146.1, 138.5, 134.2
(q, J = 34.2 Hz), 132.7 – 132.4 (m), 130.5, 130.4, 128.2, 127.0, δ 124.2
(q, J = 272.1 Hz), 123.4, 93.1, 67.7, 40.0, 22.0; IR (KBr tablet): ν = 3067
(w), 1624 (w), 1498 (w), 1455 (w), 1142 (s), 1029 (s), 850 (w), 704 (m),
639 (s) cm-1; HRMS (ESI): m/z calcd for C19H15F6IN3 [M - CF3O3S]+:
526.0209; found: 526.0207.
Synthesis of other triazolium salts is described in the Supporting
Information.
Synthesis of triazoles:
(R)-4-(3,5-bis(trifluoromethyl)phenyl)-5-iodo-1-(1-phenylethyl)-1H-
1,2,3-triazole (3a)
Acknowledgements
CuI (0.013 g, 0.068 mmol) and TBTA (0.038 mg, 0.072 mmol) were
dissolved in degassed MeCN (4.0 mL) under argon atmosphere and
stirred at r.t for 30 min. 1-(iodoethynyl)-3,5-bis(trifluoromethyl)benzene
(0.495 g, 1.36 mmol) and (R)-(1-azidoethyl)benzene (0.201 g, 1.37
mmol) dissolved in THF (2.8 mL) were added and the reaction mixture
was stirred at r.t. for 8 h., during which a brown suspension formed. The
reaction mixture was concentrated, NH4OH (10 mL, 10 % w/w) was
added and the aqueous phase was extracted with CH2Cl2 (4 x 10 mL).
The combined organic phase was dried over anhydrous Na2SO4,
concentrated and purified by column chromatography on silica gel (from
The authors thank the Estonian Ministry of Education and
Research (Grant Nos. IUT 19-32, IUT 19-9, PUT1468 and
PUT692), the Centre of Excellence in Molecular Cell
Engineering (2014-2020.4.01.15-0013) and the Academy of
Finland (K.R.: grant no. 263256, 265328 and 292746) for
financial support. We thank Ms Tiina Aid and Dr. Mati Müürisepp
for IR and MS.
5% of EtOAc in petroleum ether) to provide triazole 3a as colourless
25
crystals (0.530 g, 76% yield); M.p.: decomposes above 125 °C; [α D =
]
Keywords: Halogen-bonding, heterocycles, donor-acceptor
13.5 (c = 0.30 in chloroform); 1H NMR (400 MHz, [D1]chloroform) δ 8.46
(bs, 2H), 7.89 (bs, 1H), 7.44 – 7.24 (m, 5H), 5.82 (q, J = 7.1 Hz,1H), 2.14
(d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, [D1]chloroform) δ 147.2, 139.8,
132.6, 132.1 (q, J = 33.6 Hz), 129.2, 128.6, 127.7 – 127.5 (m), 123.4 (q,
J = 272.8 Hz), 122.2 – 122.1 (m), 122.3 – 122.0 (m)., 77.9, 62.1, 22.4; IR
systems, X-ray diffraction, NMR titration.
7
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
A general platform for the synthesis of
various chiral halogen bond donors
and characterization of factors that
influence the strength of the halogen
bond in solution is provided. Also, the
enantiodiscrimination of acceptors via
halogen bond participation is
Mikk Kaasik, Sandra Kaabel, Kadri Kriis,
Ivar Järving, Riina Aav, Kari Rissanen,
and Tõnis Kanger*
Page No. – Page No.
Synthesis and characterization of
chiral triazole-based halogen bond
donors: halogen bonds in solid state
and in solution
described.
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