Electronic substituent effects of guests on the conformational network and binding behavior of oxatub[4]arene

Article abstract of DOI:10.1021/acs.joc.7b01914

A series of quaternary ammonium guests have been synthesized, and their binding behavior with oxatub[4]arene have been studied. In particular, remote electronic substituents of the guests can significantly affect the binding affinities mainly through a field/inductive effect by following a linear free energy relationship. More surprisingly, oxatub[4]arene, with a complex conformational network, shows a large amplitude of conformational change in response to the remote electronic substituents on the guests. This novel mode of synthetic molecular recognition may also have biological relevance.

Full text of DOI:10.1021/acs.joc.7b01914

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Article
Electronic Substituent Effects of Guests on the Conformational
Network and Binding Behaviour of Oxatub[4]arene
Fei Jia, Liu-Pan Yang, Dong-Hao Li, and Wei Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01914 • Publication Date (Web): 05 Sep 2017
Downloaded from http://pubs.acs.org on September 5, 2017
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Electronic Substituent Effects of Guests on the
Conformational Network and Binding Behaviour of
Oxatub[4]arene
Fei Jia,a,b LiuꢀPan Yang,a DongꢀHao Li,a and Wei Jiang*a
a Department of Chemistry, South University of Science and Technology of China, Xueyuan Blvd 1088,
Nanshan District, Shenzhen, 518055, China.
b Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
*To whom correspondence should be addressed. Eꢀmail: jiangw@sustc.edu.cn;
RECEIVED DATE (to be automatically inserted after your manuscript is accepted)
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Abstract: A series of quaternary ammonium guests have been synthesized, and their binding behavior
with oxatub[4]arene have been studied. In particular, remote electronic substituents of the guests can
significantly affect the binding affinities mainly through a field/inductive effect by following a linear
free energy relationship. More surprisingly, oxatub[4]arene, with a complex conformational network,
shows a large amplitude of conformational change in response to the remote electronic substituents on
the guests. This novel mode of synthetic molecular recognition may also have biological relevance.
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Introduction
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Large amplitude of conformational change during molecular recognition plays a pivotal role in
biological behaviour and function, such as the allosteric effect,1 signal transduction,2 and biomolecular
machines.3 However, due to the complexity of biological systems, many aspects of the conformational
properties of bioreceptors are still unclear.4 Clarifying these aspects would help the understanding of
biological behaviour and functions. Simplified macrocyclic receptors are often regarded as models for
their natural counterparts. Numerous macrocyclic receptors with multiple conformations are known5,6
but there are rare macrocyclic receptors which are qualified as models for studying the conformational
complexity of bioreceptors,7 either due to indistinguishable/illꢀdefined conformational states or because
of poor/no binding abilities of some conformers.
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Following our interest in biomimetic molecular recognition,8 we have designed and synthesized
several conformationally adaptive macrocycles,9 , 10 one of which we named oxatub[4]arene (TA4,
10
Scheme 1a). This macrocycle possesses four wellꢀdefined conformations resulting from the
naphthalene flipping (Figure 1). The four conformers have similar cavity sizes but are easily
distinguished from each other. Each conformer can accommodate a guest. Consequently, this
macrocycle consists of a rather complex conformational network. We envisaged it could be used to
understand the influence of conformational complexity on molecular recognition. Herein, we report the
influence of the structural modification of quaternary ammonium guests 11 (Scheme 1b) on the
conformational network and molecular recognition of TA4, with an emphasis on the electronic
substituent effect of the guests on the conformational complexity of the host.
Results and Discussion
In the previous report,10b we found tetraethyl ammonium 2+ binds to TA4 even more strongly than
tetramethyl ammonium 1+ does. This is presumably due to that tetraethyl ammonium 2+ contributes
more hydrogen atoms for CꢀH⋅⋅⋅π interactions than 1+, as indicated by a more negative enthalpy term
(Table 1). On this basis, we envisioned quaternary ammoniums with two benzyl substituents could also
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be hosted by TA4. Thus, we designed and synthesized a series of quaternary ammonium guests (Scheme
1b), in particular the ones with different paraꢀsubstituents on the phenyl groups, to explore the
substituent effects of guests on the conformations and binding behaviour of TA4.
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Scheme 1. Chemical structures of (a) perꢀbutyl oxatub[4]arene (TA4) and (b) guests involved in this
research. The counterions are PF6 . Numberings on the structure of TA4 correspond to the assignments
of NMR signals.
ꢀ
The binding constants (Figure S1ꢀS31) of TA4 to these guests were determined either by isothermal
titration calorimetry (ITC, for strong binding, Ka > 1000 Mꢀ1) or by NMR titrations (for weak binding,
Ka < 1000 Mꢀ1). The data are shown in Table 1. Substituting two methyl groups in 1+ with two benzyl
groups affords guest 3+. 1H NMR experiment (Figure S32) showed that guest 3+ was strongly bound by
TA4, and the binding constant is 1.68×105 Mꢀ1. This binding constant is one order of magnitude larger
than those for 1+ and 2+. ITC results show that the higher binding affinity is mainly contributed from
entropic gain (Table 1). Replacing the two methyl groups in 3+ with two protons completely shut down
the binding, since no obvious complexationꢀinduced shift was detected when mixing TA4 with 4+ in 1:1
ratio (Figure S33). This shows the important role of the core quaternary ammonium ions in the effective
hostꢀguest complexation. Changing the methyl groups of 3+ to ethyl groups decreases the binding
constants by 2 ꢀ 3 orders of magnitude, as seen for 5+ and 6+. This indicates that 5+ and 6+ are probably
too bulky for the conformers of TA4.
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Figure 1. Chemical structures of the four conformers of TA4.10a Numberings on the structures and their
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colors correspond to the assignments of NMR signals.
To further test the substituent effect, substituent groups were installed on the phenyl groups of 3+.
Orthoꢀsubstitution (7+ꢀ10+) significantly weakens the binding, probably because the substituent groups
are too bulky and disturbing the effective complexation. Introduction of metaꢀsubstituting groups (11+ꢀ
14+) only slightly decrease the binding affinities when compared to the ones with orthoꢀsubstituent.
Orthoꢀsubstitution obviously creates more serious steric hindrance for the effective binding than metaꢀ
substitution. This is more clearly evident when one compares the binding affinities between 15+ and 16+.
The ortho/metaꢀsubstitution generally leads to weaker bindings, either through unfavourable entropy or
due to unfavourable enthalpy. Nevertheless, paraꢀsubstitution (17+ꢀ27+) generally increases the binding
affinities with only one exception (25+). This suggests that paraꢀsubstituent does not sterically disturb
the effective binding site with TA4.
The paraꢀsubstitution does not cause steric effect on the binding with TA4 and only affects the
binding through electronic substituent effects. Therefore, we can use the guests 3+ and 17+ – 27+ to study
the electronic substituent effect of guests on the binding behaviour of oxatub[4]arene for which
Hammett’s linear free energy relationship can be applied.12 The logarithm of the relative binding
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constants of 17+ – 27+ over 3+ was plotted against the Hammett parameters, such as σp, σm and σ+
(Figure 2, S34, and S35). However, only σm gave a relatively good linear relationship. Although R2 is
only 0.80, most of data are located near the line. σm is known to represent field/inductive effects. Thus,
this suggests that the binding affinities of TA4 to 17+ – 27+ were affected by the substituents through the
field/inductive effect.13 Presumably, the substituents affect the π⋅⋅⋅π stacking between the host and the
guest through the field/inductive effects.14
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Table 1. Binding constants (Mꢀ1) as determined by ITC in the 1:1 mixture of 1,2ꢀdichloroethane and
MeCN at 25 oC or by 1H NMR titration (400 MHz, CD2Cl2 : CD3CN = 1:1, 25 oC).
guests
△
G°
△
H°
ꢀT△S°
Ka (Mꢀ1)
a
(kJ⋅molꢀ1)
(kJ⋅molꢀ1)
(kJ⋅molꢀ1)
1+b
(6.39 ± 0.60) × 103
ꢀ21.8 ± 0.6
ꢀ16.6
ꢀ5.2
2+b
(9.90 ± 0.80) × 103
(1.68 ± 0.30) × 105
(5.07 ± 0.55) × 103
(4.75 ± 0.52) × 104
(1.28 ± 0.22) × 104
(3.98 ± 0.41) × 104
(3.55 ± 0.25) × 103
(3.19 ± 0.30) × 104
(2.63 ± 0.36) × 105
(1.58 ± 0.80) × 106
(1.06 ± 0.30) × 106
(4.86 ± 0.65) × 105
(5.05 ± 0.12) × 105
(6.59 ± 0.54) × 105
(8.43 ± 0.25) × 105
(1.54 ± 0.35) × 106
(2.02 ± 0.18) × 105
(1.21 ± 0.35) × 105
(1.67 ± 0.23) × 105
(3.01 ± 0.30) × 105
Ka (Mꢀ1)
ꢀ22.9 ± 0.8
ꢀ29.8 ± 0.2
ꢀ20.6 ± 0.2
ꢀ26.7 ± 0.3
ꢀ23.4 ± 0.2
ꢀ26.3 ± 0.4
ꢀ20.3 ± 0.2
ꢀ25.7 ± 0.4
ꢀ30.9 ± 0.5
ꢀ35.4 ± 0.5
ꢀ34.4 ± 0.4
ꢀ32.4 ± 0.3
ꢀ32.5 ± 0.2
ꢀ33.2 ± 0.3
ꢀ33.9 ± 0.4
ꢀ35.3 ± 0.5
ꢀ30.2 ± 0.4
ꢀ29.0 ± 0.2
ꢀ29.8 ± 0.4
ꢀ31.3 ± 0.2
ꢀ23.8
ꢀ19.8
ꢀ20.9
ꢀ12.2
ꢀ14.7
ꢀ13.2
ꢀ25.8
ꢀ18.1
ꢀ16.9
ꢀ22.0
ꢀ24.8
ꢀ20.2
ꢀ25.1
ꢀ25.6
ꢀ27.2
ꢀ26.4
ꢀ17.5
ꢀ12.9
ꢀ19.7
ꢀ25.9
guestsc
ꢀ0.9
ꢀ10.0
0.3
ꢀ14.5
ꢀ8.7
ꢀ13.1
5.5
ꢀ7.6
ꢀ14.0
ꢀ13.4
ꢀ9.6
ꢀ12.2
ꢀ7.4
ꢀ7.6
ꢀ6.7
ꢀ8.9
ꢀ12.7
ꢀ16.1
ꢀ10.1
ꢀ5.4
3+
7+
11+
12+
13+
14+
15+
16+
17+
18+
19+
20+
21+
22+
23+
24+
25+
26+
27+
guestsc
Ka (Mꢀ1)
(1.05 ±
0.08) × 102
(4.10 ± 0.3)
× 101
(3.45 ± 0.47) × 102
5+
9+
(3.46 ± 0.11) × 102
(3.90 ± 0.20) × 101
6+
8+
10+
a
b
These binding constants were determined by ITC (Figure S1ꢀS19); the binding parameters of these
c
two guests were reported (see ref 9b); these binding constants were determined by NMR titrations
(Figure S20ꢀS31).
How would the conformational network of TA4 respond to the substituents of the guests? First, we
have to distinguish the conformers of TA4 in the complexes. As reported earlier,10 the four conformers
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have different symmetries (Figure 1). Conformers II and III can be readily distinguished from each
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other and the other two conformers based on H NMR peak pattern: there are eight doublets and four
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doublets for the aromatic peaks of the host, respectively. Nevertheless, conformers I and IV cannot be
easily differentiated from each other, because the symmetries of conformers I and IV result in similar
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peak patterns in H NMR spectra: two doublets for the aromatic protons. But the 2ꢀdimensional
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arrangement of protons 2, a, and b is different for conformers I and IV and causes different Nuclear
Overhauser Effect (NOE) effects: in conformer I, proton 2 has NOE contact with proton b but not with
proton a; while in conformer IV, proton 2 is in close proximity to both protons a and b. This has been
used to distinguish the two conformers.10
For free TA4, the interconversion among the four conformers is relatively quick at the NMR
timescale.10a When a guest is encapsulated by TA4, the cavity is thus occupied. Consequently, the
conformational interconversion is stopped since the cavity is blocked. In order to allow the flipping of
naphthalene, the guest has to be released and then naphthalene can flip. This means that the rate of
conformational interconversion is determined by guest exchange rate. When the guest exchange is slow
at the NMR timescale, the conformers in the complexes could be well differentiated according to their
1H NMR spectra.
Luckily, most of the guests (3+ and 5+ – 27+) in their complexes with TA4 exchange slowly at the
NMR timescale at 25 °C (the exceptions are 6+, 8+ and 9+). Thus, the conformations can be assigned
(Figure 3 and S36) according to 1H 1H,ꢀNOESY NMR spectra (Figure S37ꢀS41), the peaks patterns and
integrals of the host and the guests (the methyl groups on the quaternary ammonium groups appear in
the region of 0.0 ꢀ 1.2 ppm), and extensive comparison. Among guests 5+ – 16+, more bulky guests (5+,
7+, 10+ and 15+) prefer conformer IV, since they require a larger cavity to be accommodated and
conformer IV has the largest cavity among the four conformers (Figure 1). For other guests (11+ – 14+
and 16+), conformer II appear together with conformer IV to maximize the binding.
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Figure 2. Binding affinities of guests 17+ꢀ27+ (KX) relative to guest 3+ (KH) as a function of Hammett
parameter σm (ρ = 1.4 ± 0.2).
The conformer distribution of TA4 in the presence of guests 3+ or 17+ – 27+ is summarized in Figure
4. The guests with electronꢀwithdrawing substituents (NO2 and CN) tend to induce conformer I. With
decreasing the electronꢀwithdrawing ability of the substituents, the percentages of conformers II and IV
start to increase and that of conformer I decreases. With respect to the halogen substituents and the
related (F, Cl, Br, I, CF3), the conformer distribution is largely unchanged with conformers I and II as
the major ones. In contrast, the guests with electronꢀdonating substituents (OMe, Me, C(Me)3) and 3+
are in favour of conformer IV. The exception is the guest with methylthio (MeS) substituent (27+), for
which conformer II is the major conformer for TA4. Steric effect can be ruled out because the bulkier
substituents do not induce more conformer IV than less bulky substituents (for examples, tꢀbutyl vs.
methyl; MeS vs. MeO; CF3/NO2 vs. halogens/H). As a consequence, only slight change of the
substituent group on the remote position of guest 3+ significantly influenced the conformational states of
TA4 in the complexes.
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Figure 3. Partial 1H NMR spectra (400 MHz, CD2Cl2:CD3CN = 1:1, 2.0 mM, 25 oC) of TA4 in
the absence or the presence of one equiv of individual guest 3+ or 17+ 27+
ꢀ
.
Figure 4. Conformer distribution of TA4 in the presence of one equiv of quaternary ammonium guests
with different electronic substituent groups (3+ and 17+ ꢀ 27+). [I] + [II] + [IV] = 100%.
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17+ and 26+ are two representative guests and prefer conformers I and IV, respectively. In order to
rationalize the underlying reason, computation was performed on the complexes 17+@TA4-I and
26+@TA4-IV. Their energyꢀminimized structures were shown in Figure 5. As mentioned above, the
core binding site is the quaternary ammoniums and the attached methyl or methylene groups. CꢀH⋅⋅⋅O,
CꢀH⋅⋅⋅π, and cation⋅⋅⋅π interactions between the quaternary ammonium core and TA4 are indeed
observed for both 17+@TA4-I and 26+@TA4-IV. Differently, the phenylene groups of guest 17+ are
more heavily involved in the interactions with TA4 through CꢀH⋅⋅⋅O, CꢀH⋅⋅⋅π, and π ⋅⋅⋅π interactions
than guest 26+. The cavity size of conformer I is smaller than that of conformer IV. Therefore, it is
better for conformer I to interact with the phenylene groups on the guests. While the larger cavity allows
conformer IV to better accommodate the quaternary ammonium core. This may explain why guests
with electronꢀdeficient and electronꢀrich substituents prefer conformer I and IV, respectively.
Conformer II share very similar cavity size and structure with conformer I, and therefore shows similar
preference to the substituents.
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Although such large amplitudes of conformational changes were induced by the remote substituents,
the binding constants still reasonably follow the linear free energy relationship, and the substituent
groups affect the binding affinity mainly through the field/inductive effect. In other words, the conforꢀ
mational network of oxatub[4]arene shows response to the subtle changes on the field/inductive effect of
the remote substituents.
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Figure 5. Energyꢀminimized structures of 17+@TA4-I and 26+@TA4-IV using the Semiempirical
PM6 level of theory (Spartan ’14, Wavefunction, Inc.). Butyl groups of TA4 were shorted to methyl
groups for viewing clarity.
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Conclusions
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In summary, we synthesized a series of quaternary ammonium ion guests with different substituent
groups and studied the influence of substituent groups of the guests on the binding behaviour and
conformational networks of oxatub[4]arene. The paraꢀsubstitution can affect the binding affinities
through a field/inductive effect by following a linear free energy relationship. Surprisingly,
oxatub[4]arene undergoes a large amplitude of conformational changes in response to the remote
substituents. To the best of our knowledge, this is the first time that such an effect was observed in
synthetic molecular recognition. We believe this novel mode of synthetic molecular recognition may
also have biological relevance.1a,15
Experimental Section
General Methods. All the reagents involved in this research were commercially available and used
without further purification unless otherwise noted. Solvents were either employed as purchased or dried
prior to use by standard laboratory procedures. Thinꢀlayer chromatography (TLC) was carried out on
0.25 mm Yantai silica gel plates (60Fꢀ254). Column chromatography was performed on silica gel 60
(Tsingdao 40 – 63 nm, 200 – 300 mesh). 1H, 13C NMR, and 1Hꢀ1H ROESY NMR spectra were recorded
on Bruker Avanceꢀ400/500 spectrometers. All chemical shifts are reported in ppm with residual solvents
or TMS (tetramethylsilane) as the internal standards. The following abbreviations were used for signal
multiplicities: s, singlet; d, doublet; t triplet; m, multiplet. Electrosprayꢀionization timeꢀofꢀflight highꢀ
resolution mass spectrometry (ESIꢀTOFꢀHRMS) experiments were conducted on an applied Q
EXACTIVE mass spectrometry system. Guests 3+, 4+, 6+, 7+, 19+, 20+, 24+ and 26+ were synthesized by
following the literature procedures.16
Synthetic Procedures.
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Compound 5ꢀPF6. Benzyl bromide (1.0 g, 5.9 mmol) and NꢀBenzylꢀNꢀEthylmethyl amine (872.5 mg,
5.9 mmol) were mixed in acetonitrile (30 mL), and the resulting solution was stirred at 90oC for 12h.
After cooling to room temperature, the reaction mixture was concentrated. A small amount of diethyl
ether was added to the residual solution. The precipitate was filtered off to give 5ꢀBr as a white powder,
which was used directly in the next step. The solution of 5ꢀBr in deionized water was added dropwise
into the saturated aqueous solution of NH4PF6. After stirring for 1 h, the precipitate was collected
through filtration, washed with deionized water and dried in vacuum to give 5ꢀPF6 as a white powder
(250 mg, 25% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.63ꢀ7.50 (m, 10H), 4.50ꢀ4.37 (m,
4H), 3.24 (q, J =7.2Hz, 2H), 2.81 (s, 3H), 1.47 (ddd, J =7.3, 5.6, 1.8 Hz). 13C NMR (100 MHz, CD3CN,
298 K) δ [ppm] = 133.1, 130.7, 129.2, 127.2, 65.2, 56.0, 45.8, 7.7. ESIꢀTOFꢀHRMS: m/z calcd for [Mꢀ
PF6]+ C17H22N+, 240.1747; found 240.1744 (error = ꢀ1.2 ppm).
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General synthetic procedure for compounds 8ꢀPF6, 9ꢀPF6, 10ꢀPF6, 11ꢀPF6, 12ꢀPF6, 13ꢀPF6, 14ꢀPF6,
15ꢀPF6, 16ꢀPF6, 21ꢀPF6, 22ꢀPF6 and 25ꢀPF6. Aromatic quaternary ammonium (QA)
hexafluorophosphates were synthesized by using the procedure reported by Rissanen and coworkers.16a
The corresponding benzyl bromide (200 mg) and DMF (10 mL) were mixed and the resulting solution
was stirred at 80oC for 48h. After cooling to room temperature, the solution was concentrated. A small
amount of diethyl ether was added to the residual solution. The resulting precipitate was filtered off to
give the corresponding QA bromides as white powder, which was used directly in the next step. The
solution of QA bromides in deionized water was added dropwise into the saturated aqueous NH4PF6.
After stirring for 1 h, the precipitate was collected through filtration, washed with deionized water and
dried in vacuum to give the corresponding QA hexafluorophosphates.
8ꢀPF6: white powder (160 mg, 40% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 8.06 (dd, J =
8.0, 1.2 Hz, 2H), 7.61 (dd, J = 7.8, 1.7 Hz, 2H), 7.53 (td, J = 7.6, 1.3 Hz, 2H), 7.28 – 7.22 (m, 2H), 4.75
(s, 4H), 3.04 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ [ppm] = 141.5, 134.7, 132.7, 130.4, 129.3,
104.2, 71.7, 49.8. ESIꢀTOFꢀHRMS m/z calcd for [MꢀPF6]+ C16H18I2N+, 477.9523; found 477.9517 (error
= ꢀ1.3 ppm).
9ꢀPF6: white powder (210 mg, 55% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.84 (dd, J =
7.9, 1.4 Hz, 2H), 7.70 (dd, J = 7.7, 1.8 Hz, 2H), 7.57 (td, J = 7.5, 1.5 Hz, 2H), 7.51 (td, J = 7.7, 1.8 Hz,
13
2H), 4.80 (s, 4H), 3.06 (s, 6H). C NMR (100 MHz, CD3CN, 298 K) δ [ppm] = 135.7, 134.4, 132.9,
128.6, 127.4, 127.1, 67.4, 49.4. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+ C16H18Br2N+, 381.9801; found
381.9800 (error = ꢀ0.3 ppm).
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10ꢀPF6: white powder (200 mg, 54% yield). H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.42ꢀ7.34
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(m, 6H), 4.57 (s, 4H), 2.98 (s, 6H). C NMR (100 MHz, CD3CN, 298 K) δ [ppm] = 159.7 (dd, JFC
=
8.4, 3.9 Hz), 157.3 (dd, JFC = 12.3, 4.3 Hz), 121.2 (dd, JFC = 24.2, 3.7 Hz), 120.3 (dd, JFC = 23.7, 10.0
Hz), 118.1 (dd, JFC = 25.2, 9.3 Hz), 116.0 (dd, JFC = 16.6, 8.6 Hz), 61.6, 49.0. ESIꢀTOFꢀHRMS: m/z
calcd for [MꢀPF6]+ C16H16F4N+, 298.1213; found 298.1209 (error = ꢀ1.3 ppm).
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11ꢀPF6: white powder (205 mg, 54% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.43 (d, J =
6.5 Hz, 4H), 7.37 – 7.30 (m, 4H), 4.43 (s, 4H), 2.86 (s, 6H), 2.42 (s, 6H). 13C NMR (100 MHz, CD3CN,
298 K) δ [ppm] = 139.3, 133.7, 131.4, 130.1, 129.1, 127.2, 68.5, 48.7, 48.61, 48.57, 20.3. ESIꢀTOFꢀ
HRMS: m/z calcd for [MꢀPF6]+ C18H24N+, 254.1903; found 254.1895 (error = ꢀ3.1 ppm).
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12ꢀPF6: white powder (87 mg, 24% yield). 1H NMR (500 MHz, CD3CN, 298 K) δ [ppm] = 7.93 (d, J =
7.8 Hz, 2H), 7.87 (s, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.77 (t, J = 7.8 Hz, 2H), 4.57 (s, 4H), 2.94 (s, 6H).
13C NMR (125 MHz, CD3CN, 298 K) δ [ppm] = 137.1, 130.9 (q, JFC = 32.5 Hz), 129.7 (q, JFC = 3.9
Hz), 127.6 (q, JFC = 3.7 Hz), 123.9 (q, JFC = 32.5 Hz), 67.6, 48.8. ESIꢀTOFꢀHRMS: m/z calcd for [Mꢀ
PF6]+ C18H18F6N+, 362.1338; found 362.1326 (error = ꢀ3.3 ppm).
13ꢀPF6: white powder (150 mg, 42% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.47 (t, J =
13
7.9 Hz, 2H), 7.17 – 7.09 (m, 4H), 7.07 (t, J = 2.2 Hz, 2H), 4.45 (s, 4H), 3.86 (s, 6H), 2.91 (s, 6H). C
NMR (100 MHz, CD3CN, 298 K) δ [ppm] =160.1, 130.3, 128.6, 125.2, 118.5, 116.3, 68.5, 55.2, 49.0,
48.92, 48.88. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+ C18H24NO2 , 286.1802; found 286.1793 (error =
+
ꢀ3.0 ppm).
14ꢀPF6: white powder (180 mg, 48% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] =7.24 (s, 2H),
7.12 (s, 4H), 4.36 (s, 4H), 2.83 (s, 6H), 2.37 (s, 12H). 13C NMR (100 MHz, CD3CN, 298 K) δ [ppm] =
139.0, 132.1, 130.7, 127.1, 68.6, 68.59, 68.57, 48.70, 48.66, 48.6, 20.2. ESIꢀTOFꢀHRMS: m/z calcd for
[MꢀPF6]+ C20H28N+, 282.2216; found 282.2213 (error = ꢀ1.1 ppm).
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15ꢀPF6: white powder (180 mg, 48% yield). H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 8.29 (d, J
=8.5 Hz, 2H), 8.17 (d, J =8.3 Hz, 2H), 8.08 (d, J =8.1 Hz, 2H), 7.81 (d, J =7.1 Hz, 2H), 7.77ꢀ7.60 (m,
6H), 5.16 (s, 4H), 2.92 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ [ppm] = 134.24, 134.20, 133.03,
132.02, 129.4, 127.8, 126.5, 125.3, 123.4, 65.1, 49.4. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+
C24H24N+, 326.1903; found 326.1898 (error = ꢀ1.5 ppm).
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16ꢀPF6: white powder (58 mg, 15% yield). H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 8.12ꢀ8.08
(m, 2H), 8.04 (d, J = 8.5 Hz, 2H), 8.02ꢀ7.97 (m, 4H), 7.68ꢀ7.61 (m, 4H), 7.59 (dd, J = 8.5, 1.9 Hz, 2H),
13
4.68 (s, 4H), 2.97 (s, 6H). C NMR (100 MHz, CD3CN, 298 K) δ [ppm] = 134.0, 133.8, 133.0, 129.3,
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128.9, 128.5, 127.9, 127.7, 127.1, 124.8, 68.60, 68.57, 68.5, 48.82, 48.78, 48.7. ESIꢀTOFꢀHRMS: m/z
calcd for [MꢀPF6]+ C24H24N+, 326.1903; found 326.1898 (error = ꢀ1.5 ppm).
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21ꢀPF6: white powder (220 mg, 60% yield). H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.60ꢀ7.55
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(m, 4H), 7.52 (d, J = 8.2 Hz, 4H), 4.45 (s, 4H), 2.86 (s, 6H). C NMR (100 MHz, CD3CN, 298 K) δ
[ppm] = 136.6, 134.8, 129.3, 126.0, 67.4, 48.52, 48.48, 48.4. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+
C16H18Cl2N+, 294.0811; found 294.0807 (error = ꢀ1.4 ppm).
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22ꢀPF6: white powder (260 mg, 70% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.73 (d, J =
8.4 Hz, 4H), 7.44 (d, J = 8.5 Hz, 4H), 4.43 (s, 4H), 2.86 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ
[ppm] = 135.0, 132.4, 126.4, 125.0, 67.5, 48.6. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+ C16H18Br2N+,
381.9801; found 381.9800 (error = ꢀ0.3 ppm).
25ꢀPF6: white powder (64 mg, 17% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.59 (d, J =
13
8.0 Hz, 4H), 7.45 (d, J = 8.0 Hz, 4H), 4.43 (s, 4H), 2.83 (s, 6H), 3.36 (s, 18H). C NMR (100 MHz,
CD3CN, 298 K) δ [ppm] = 154.1, 132.8, 126.2, 124.3, 68.2, 68.1, 68.1, 48.4, 48.4, 48.3, 34.5, 30.4. ESIꢀ
TOFꢀHRMS: m/z calcd for [MꢀPF6]+ C24H36N+, 338.2842; found 338.2837 (error = ꢀ1.5 ppm).
General synthetic procedure for compounds 17ꢀPF6, 18ꢀPF6, 23ꢀPF6 and 27ꢀPF6. The mixture of the
substituted benzyl bromide and dimethylamine (aqueous soluiton) in 1:8 in acetonitrile was stirred at
room temperature for 48h. The solution was concentrated. A small amount of diethyl ether was added
and the resulting precipitate was filtered to give the corresponding QA bromides as white powder, which
was used directly in the next step. The solution of QA bromides in deionized water was added dropwise
into the saturated aqueous solution of NH4PF6. After stirring for 1 h, the precipitate was collected
through filtration, washed with deionized water and dried in vacuum to give the corresponding QA
hexafluorophosphates.
17ꢀPF6: white powder (220 mg, 60% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 8.36 (d, J =
8.7 Hz, 4H), 7.79 (d, J = 8.7 Hz, 4H), 4.61 (s, 4H), 2.95 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ
+
[ppm] = 149.5, 134.6, 133.7, 124.1, 67.3, 49.1. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+ C16H18N3O4 ,
316.1292; found 316.1287 (error = ꢀ1.6 ppm).
18ꢀPF6: white powder (165 mg, 45% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.92 (d, J =
8.3 Hz, 4H), 7.69 (d, J = 8.3 Hz, 4H), 4.53 (s, 4H), 2.90 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ
[ppm] = 134.0, 133.0, 131.9, 117.9, 114.4, 67.6, 49.0. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+
+
C18H18N3 , 276.1495; found 276.1491(error = ꢀ1.4 ppm).
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23ꢀPF6: white powder (170 mg, 45% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.92 (d, J =
8.3 Hz, 4H), 7.29 (d, J = 8.4 Hz, 4H), 4.41 (s, 4H), 2.85 (s, 6H). 13C NMR (100 MHz, CD3CN, 298 K) δ
[ppm] = 138.4, 134.9, 126.9, 97.1, 67.7, 48.6. ESIꢀTOFꢀHRMS: m/z calcd for [MꢀPF6]+ C16H18I2N+,
477.9523; found 477.9514 (error = ꢀ1.9 ppm).
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27ꢀPF6: white powder (320 mg, 87% yield). 1H NMR (400 MHz, CD3CN, 298 K) δ [ppm] = 7.44 (d, J =
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8.6 Hz, 4H), 7.39 (d, J = 8.5 Hz, 4H), 4.41 (s, 4H), 2.84 (s, 6H), 2.54 (s, 6H). C NMR (100 MHz,
CD3CN, 298 K) δ [ppm] = 142.7, 133.4, 125.8, 123.2, 67.9, 48.3, 48.3, 48.2, 14.0. ESIꢀTOFꢀHRMS:
+
m/z calcd for [MꢀPF6]+ C18H24NS2 , 318.1345; found 318.1340 (error = ꢀ1.6 ppm).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jiangw@sustc.edu.cn
ORCID
Wei Jiang: 0000ꢀ0001ꢀ7683ꢀ5811
Notes
The authors declare no competing financial interest.
Acknowledgements. This research was financially supported by the National Natural Science
Foundation of China (No. 21572097), the Thousand Young Talents Program, and the Shenzhen special
funds for the development of biomedicine, internet, new energy, and new material industries (No.
JCYJ20160226192118056, JCYJ20170307105848463). Fei Jia is grateful to the China Scholarship
Council (CSC) for a Ph.D. fellowship.
1
Supporting Information Available. Binding constants determinations, H,1HꢀROESY NMR spectra,
and Hammett plots. This material is available free of charge via the Internet at http://pubs.acs.org.
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