Relayed Proton Brake in N-Pyridyl-2-iso-propylaniline Derivative: Two Brakes with One Proton

Article abstract of DOI:10.1021/acs.joc.0c00284

The addition of methanesulfonic acid to N-(2,6-dimethylpyridin-4-yl)-N-methyl-2-iso-propylaniline led to the selective protonation of the pyridine nitrogen atom, resulting in a significant deceleration of the rotation rates around both N-pyridyl and N-(i-

Full text of DOI:10.1021/acs.joc.0c00284

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Note
Relayed Proton Brake in N-Pyridyl-2-iso-
propylaniline Derivative: Two Brakes with One Proton
Gaku Furukawa, Takeshi Shirai, Yuki Homma, Elsa Caytan, Nicolas
Vanthuyne, Daniel FARRAN, Christian Roussel, and Osamu Kitagawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00284 • Publication Date (Web): 05 Mar 2020
Downloaded from pubs.acs.org on March 6, 2020
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Relayed Proton Brake in N-Pyridyl-2-iso-propylaniline
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Derivative: Two Brakes with One Proton
Gaku Furukawa†, Takeshi Shirai†, Yuki Homma†, Elsa Caytan*‡, Nicolas Vanthuyne§, Daniel Farran§,
Christian Roussel*§ and Osamu Kitagawa*†
†Department of Applied Chemistry (Japanese Association of Bio-intelligence for Well-being), Shibaura
Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan.
‡Institut des Sciences Chimiques de Rennes, 35000, Rennes, France
§Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Cedex 20, Marseille,
France.
†E-mail: kitagawa@shibaura-it.ac.jp
‡E-mail : elsa.caytan@univ-rennes1.fr
§E-mail: christian.roussel@univ-amu.fr
RECEIVED DATE
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TOC graphics
ΔG‡
11.6 kcal/mol
=
Me
ΔG‡
17.3 kcal/mol
=
Me
N
HN
Me
MeSO3H
Me
Me
N
Me
N
“relayed
proton brake"
i-Pr
ΔG‡
21.0 kcal/mol
i-Pr
ΔG‡
=
=
brake
15.5 kcal/mol
deceleration
ABSTRACT: The addition of methane sulfonic acid to N-(2,6-dimethylpyridin-4-yl)-N-methyl-2-iso-
propylaniline led to the selective protonation of the pyridine nitrogen atom, resulting in a significant
deceleration of the rotation rates around both N-pyridyl and N-(i-Pr)phenyl bonds through a relayed
brake mechanism.
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Molecular rotors, which can control the rate and direction of bond rotation by external
stimuli, have received much attention in the field of molecular device.1 Molecular brakes are
one of the most fascinating classes of the molecular rotors, and the deceleration of a bond
rotation has been achieved by a various external stimuli such as metal cations, acids, bases,
halide anions, light and heat.2 On the other hand, as far as we know, molecular brake involving
the rotational deceleration of plural bonds upon a single protonation has so far not been reported.
Recently we found that in N-C axially chiral 2-tert-butyl-6-methylanilines I bearing various para-
substituted phenyl groups on nitrogen atom, the rotational barriers around a chiral axis increase with
electron-withdrawing ability of para-substituents X (Figure 1).3 Furthermore, on the basis of these
results, a new type of molecular brake (remote proton brake) was developed.3,4 That is, the addition of
methane sulfonic acid to N-(4-aminophenyl)-2-iso-propylaniline II selectively protonated the primary
amino group (the conversion of the electron-donating amino group into the electron-attracting
ammonium group) to bring about a considerable increase in the rotational barrier around N-(i-Pr)Ph
bond (4 kcal/mol). This brake thus resulted from a remote structural change at the Ar [(4-NH2)Ph]
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group but not at the rotating Ar [N-(i-Pr)Ph] group.
(Previous work)
high
X
H3N
H2N
X
?
NO2
CO2Et
Cl
Me
n-Pr
n-Pr
N
N
N
H+
ΔG‡
t-Bu
Me
i-Pr
brake of
4 kcal/mol
i-Pr
H
"proton
brake"
Me
“chiral
axis”
II-H+
NH2
I
II
low
ΔG‡ = 12.8 kcal/mol
ΔG‡ = 8.8 kcal/mol
(This work)
Me
Me
significant
brake
N
Me
HN
Me
Me
H+
Me
N
N
“relayed
proton brake"
i-Pr
i-Pr
brake
significant
brake
deceleration
Figure 1. Correlation between the rotational barriers and the electronic effects in N-C axially chiral
anilines, and the application to proton brakes.
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In this paper, we report the effect of protonation on the stereodynamics of N-methyl-2-iso-
propylanilines bearing a 2- or 4-pyridyl group on the nitrogen atom. It was revealed that aniline having
a 4-pyridyl group leads to the more considerable brake than 2-pyridyl derivative upon protonation.
Furthermore, in 4-pyridyl derivative, a double brake phenomenon, where the rotations around two N-Ar
bonds are synchronously decelerated under a single protonation (relayed proton brake), was found.
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In line with our previous findings in aniline derivatives I and II, we envisioned that N-pyridyl-2-
iso-propylaniline derivatives would also lead to proton brake around N-(i-Pr)Ph bond through the
selective protonation of the remote basic pyridine nitrogen. In addition, the strong electron-withdrawing
character of the pyridyl group was expected to produce measurable rotational barriers around both the
N-pyridyl and N-(i-Pr)Ph bonds allowing the experimental determination of barriers about two N-Ar
bonds in the neutral and protonated states. Although the synthesis of N-(4-pyridyl)-2-iso-propylaniline
was initially attempted, the coupling reaction of 2-iso-propylaniline with 4-halopyridine did not
efficiently proceed.5 On the other hand, Buchwald-Hartwig amination of iso-propylaniline with 2-
bromopyridine or 4-bromo-2,6-dimethylpyridine proceeded smoothly,6 and subsequent N-methylation
gave the desired N-methyl-N-pyridyl-2-iso-propylanilines 1 and 2 in good yields (Scheme 1).
Me
1) 4-Br-2,6-Me2-
pyridine
BINAP-
Pd(OAc)2 cat.
i-Pr tert-BuONa
1) 2-Br-pyridine
BINAP-
Pd(OAc)2 cat.
tert-BuONa
N
N
NH2
Me
Me
Me
N
N
i-Pr
i-Pr
2) NaH, Me-I
2) NaH, Me-I
2 (88%)
1 (70%)
Scheme 1. Synthesis of N-methyl-N-pyridyl-2-iso-propylaniline derivatives 1 and 2.
1
At room temperature, the H-NMR peak corresponding to the two Me hydrogens of iso-
propyl group in 2-pyridyl aniline
1 was broadened (Figure 2). When MeSO3H (1.0 equiv) was
added to in toluene-d8, the broad signal was splitted into two doublet signals. The non-
1
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equivalency of two Me signals revealed an axial chirality owing to the rotational restriction
around N-(i-Pr)Ph bond at the time scale of NMR in 1-H+
.
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Me x 2
N
Me
N
CHMe2
1
1.0 equiv
MeSO3H
toluene-d8
NH
Me
Me
Me
N
CHMe2
1-H+
Figure 2. Signals of two Me groups in 1H-NMR of 1 and 1-H+ at rt.
Variable temperature NMR (VT-NMR) experiments of 1 and 1-H+ were further conducted for the
evaluation of the rotational barriers (Figure 3). In aniline 1, the broad Me signal of i-Pr at 295 K was
changed into a sharp doublet signal indicating quick N-(i-Pr)Ph bond rotation around 330 K, while it
splitted into two doublet signals revealing an axial chirality around 280 K. In pyridinium derivative 1-
H+, non-equivalent two Me signals at 295 K were coalesced around 350 K. On the basis of the VT-
NMR charts and the line shape simulation with WinDNMR,7 the rotational barriers around N-(i-Pr)Ph
bond in 1 and 1-H+ were evaluated to be 15.1 and 17.2 kcal/mol, respectively. Although the rotational
barriers of 1 and 1-H+ bearing electron-withdrawing 2-pyridyl and 2-pyridinium groups were much
higher than those of 4-aminophenyl derivatives II and II-H+ (8.8 and 12.8 kcal/mol), the magnitude of
proton brake in 1 (2.1 kcal/mol) decreased in comparison with that of II (4.0 kcal/mol).
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N
NH
Me
1.3 equiv
MeSO3H
Me
N
N
toluene-d8
CHMe2
CHMe2
1-H+
ΔG‡
15.1 kcal/mol
=
ΔG‡
17.2 kcal/mol
=
8
1
9
350K
340K
330K
320K
315K
310K
305K
300K
295K
290K
285K
280K
275K
270K
265K
260K
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Figure 3. VT-NMR chart of two Me groups in 1 and 1-H+ in toluene-d8 and the rotational barriers
around N-(i-Pr)Ph bond.
In (2,6-dimethylpyridin-4-yl)-2-iso-propylaniline 2, two hydrogens (and two Me groups) on
pyridine ring and two Me groups of iso-Pr in aniline 2 showed equivalent NMR signals at rt in toluene-
d8, while the addition of MeSO3H (1.3 equiv) to 2 resulted in the formation of non-equivalent hydrogen
signals (Figure 4). The non-equivalency of pyridinium hydrogens and i-Pr Me groups should be due to
the rotational restriction around N-pyridinium bond and N-(i-Pr)Ph bond, respectively.8 Especially, for
two hydrogens on pyridininium ring, a significant difference of the chemical shift was observed (Dd =
1.15 ppm). This may indicate that pyridinium ring and iso-Pr-phenyl ring in 2-H+ are co-planar and
perpendicular, respectively, toward the nitrogen plane [Me-N-C4(Py)-C1(i-Pr)Ph plane]. It results that
the two hydrogens (Hb: d = 5.45 ppm, Ha: d = 6.50 ppm) on pyridinium ring are located inside and
outside of the iso-Pr-phenyl ring cone, respectively. In proton free 2, since the rotation around N-
pyridyl bond frequently occurs, the two hydrogens on the pyridine gave a single signal at average
chemical shift (ca. 6.0 ppm) between Ha and Hb.
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Me
H
Me
Hb
H
N
Ha
N
N
HN
Me
1.3 equiv
MeSO3H
Me
CHMe2
Me
Me
toluene-d8
CHMe2
2-H+
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2
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H x 2
Hb
Ha
Me
Me
Me x 2
Figure 4. 1H-NMR signals of 2 and 2-H+ in toluene-d8 at rt.
VT-NMR experiment of 2 and 2-H+ and the line-shape simulation were subsequently performed
(Figure 5). In aniline 2 in toluene-d8, equivalent hydrogens of pyridine ring and i-Pr group at 300 K
were changed to non-equivalent hydrogens around 240 K and 270 K, respectively, and the rotational
barriers around N-pyridyl and N-(i-Pr)Ph bonds were evaluated to be 11.6 and 15.5 kcal/mol,
respectively. The barrier about N-(i-Pr)Ph bond in 4-pyridyl derivative 2 is similar to that in 2-pyridyl
derivative 1 (15.1 kcal/mol).
For non-equivalent hydrogens of pyridinium ring and i-Pr group in 2-H+, the broadening and
sharpening of NMR signals were observed, respectively, with increasing temperature, while two Me
signals of i-Pr were slightly broadened at 370 K.9 Full coalescence of these non-equivalent signals was
not attained even at 370 K (limited heating temperature of toluene-d8), indicating high rotational barriers
for these N-Ar bonds. Nevertheless, the rotational barrier of the N-pyridinium bond in 2-H+ was
evaluated to be 17.3 kcal/mol through the line-shape simulation, and this value was 5.7 kcal/mol higher
than that in 2. The 5.7 kcal/mol corresponds to the neat proton brake affecting the pyridine motif
rotation on going from 2 to 2-H+. For N-(i-Pr)Ph bond in 2-H+, the rotational barrier could be evaluated
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by the line-shape simulation of the doublet signal at the limit temperature (370K). The rotational barrier
was revealed to be 21.0 kcal/mol which is 5.5 kcal/mol higher than that in 2. This value (5.5 kcal/mol)
corresponds to the neat relayed brake affecting the N-(i-Pr)Ph bond rotation on going from 2 to 2-H+. It
is noteworthy that the magnitude of proton brake around N-(i-Pr)Ph bond in 4-pyridyl derivative 2 (5.5
kcal/mol) is considerably larger than that in 2-pyridyl derivative 1 (2.1 kcal/mol), while the reason is
unclear at the present time.
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2H
2Me
*
320K
310K
*
*
ΔG‡
11.6 kcal/mol
=
Me
H
300K
290K
280K
270K
260K
250K
H
N
=
*
*
Me
Me
N
CHMe2
*
*
ΔG‡
2
15.5 kcal/mol
240K
230K
*
*
*
*
1.3 equiv
MeSO3H
toluene-d8
2Me
2H
*
*
370K
360K
350K
*
*
*
*
*
*
*
*
*
*
*
*
*
*
ΔG‡
17.3 kcal/mol
=
Me
340K
330K
320K
310K
H
HN
Me
Me
N
H
CHMe2
*
*
*
ΔG‡
21.0 kcal/mol
=
2-H+
300K
290K
280K
*
Figure 5. VT-NMR chart of hydrogens on pyridine ring and Me hydrogens in 2 and 2-H+ in toluene-d8.
VT-NMR measurement of 2 and 2-H+ in DMSO-d6 followed by the line-shape simulation were also
performed. The high melting point of DMSO-d6 did not allow the determination of the barrier for the
N-pyridine bond in 2 but the three other barriers around N-(i-Pr)Ph (DG‡ = 15.3 kcal/mol) bond in 2, N-
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pyridinium bond (DG‡ = 17.2 kcal/mol) in 2-H+ and N-(i-Pr)Ph bond (DG‡ = 21.4 kcal/mol) in 2-H+
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were nicely evaluated thank to the higher range of attainable temperatures. They all were very slightly
higher (0.4 kcal/mol) than those determined in toluene-d8 revealing a very weak solvent effect (see SI).
Furthermore, the similarity of the barriers in a weakly dissociating solvent such as toluene-d8 and a
strongly dissociating solvent such as DMSO-d6 clearly shows that the barriers evolve from the same
molecular entities in the two solvents. A conjectural contribution of ion pairs or H-bonded complexes
in barrier determination for 2-H+ in toluene-d8 can be ruled out. In summary, going from 2 to 2-H+, the
rotation rates around two N-C axes are considerably decelerated by a single protonation.
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The significant double brakes observed in 4-pyridyl derivative 2 may be rationalized in accordance
with Figure 6. The addition of MeSO3H to 2 leads to a selective protonation of the pyridine nitrogen to
generate 2-H+. In 2-H+, the double bond character about an N-pyridinium bond is increased by strong
resonance of the lone electron pair on tert-amino group with pyridinium ring, leading to the significant
increase in the rotational barrier. The rotational brake around N-pyridinium bond also remarkably
influences the rotation around an N-(i-Pr)Ph bond. We previously reported the rotational mechanism
around N-Ar bond in N-(4-aminophenyl)-2-substituted-anilines based on DFT calculation.3 It indicates
that in the transition state during N-Ar(2-substituted-phenyl) bond rotation, 4-aminophenyl group is
largely twisted because of the alleviation of the steric repulsion with an ortho-substituent on 2-
substituted-phenyl group. Similarly, the twisting of pyridyl group would be required for N-(i-Pr)Ph
bond rotation in 2 and 2-H+. The energy for the twisting of pyridinium group in 2-H+ should be higher
than that of pyridyl group in 2 due to the increase in the double bond character of N-pyridinium bond in
2-H+. As a result, the rotational barrier around N-(i-Pr)Ph bond in 2-H+ is significantly increased. In
such interlocking controlled rotational mechanism, the change in rotational barriers around N-(i-Pr)Ph
bond may be determined by the change in barrier for N-pyridyl bond rotation. Namely, the proton brake
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in N-(i-Pr)Ph and N-pyridyl bonds would possess a similar magnitude. Indeed, the brake magnitude of
N-(i-Pr)Ph bond (5.5 kcal/mol) was very close to that of N-pyridyl bond (5.7 kcal/mol).
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9
Me
Me
Me
brake of
5.7 kcal/mol
HN
Me
HN
Me
N
Me
Me
N
Me
i-Pr
N
Me
N
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i-Pr
i-Pr
brake of
5.5 kcal/mol
2
2-H+
‡
‡
Me
Me
HN
N
Me
Me
Me
Me
N
N
i-Pr
i-Pr
lower ΔG‡
higher ΔG‡
‡
‡
Me
Me
N
HN
Me
Me
Me
Me
N
N
H
H
i-Pr
i-Pr
lower ΔG‡
higher ΔG‡
Figure 6. Transition state model for the N-Ar bond rotation in 2 and 2-H+.
CONCLUSION
We succeeded in the development of proton brake molecules through the protonation of N-methyl-
2-iso-propylanilines bearing a 2- or 4-pyridyl group on the nitrogen atom. The brake magnitude in 4-
pyridyl derivative was more considerable than that of 2-pyridyl derivative. Furthermore, in 4-pyridyl
derivative, it was found that the rotation rates around two N-Ar bonds are remarkably decelerated by a
single protonation. The deceleration of two N-Ar bond rotations proceeds via a relayed mechanism in
which the brake of an N-Ar (N-pyridyl) bond also causes the brake of an another N-Ar [N-(i-Pr)Ph]
bond.10 To the best of our knowledge, this work is the first example on communicating molecular
brakes. This brake system is similar to that of a penny farthing bike in which the rotational speeds of
two wheels having different size (different rotational barriers) are synchronously decreased by a single
front brake (Figure 1).11
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EXPERIMENTAL SECTION
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1H and 13C NMR spectra were recorded on a 400 MHz spectrometer. In 1H and 13C NMR spectra,
chemical shifts were expressed in d (ppm) downfield from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm),
respectively. HRMS were recorded on a double focusing magnetic sector mass spectrometer using
electron impact ionization. Column chromatography was performed on silica gel (75-150 mm).
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N-Methyl-N-(2-pyridyl)-2-iso-propylaniline (1). Under N2 atmosphere, Pd(OAc)2 (9 mg, 0.04 mmol)
and rac-BINAP (50 mg, 0.08 mmol) in toluene (0.5 mL) were stirred for 10 min at rt. 2-iso-
Propylaniline (135 mg, 1.0 mmol) in toluene (1.5 mL), t-BuONa (144 mg, 1.5 mmol) and 2-
bromopyridine (98 µL, 1.0 mmol) were added to the reaction mixture, and the mixture was stirred for 3
h at 80 °C (oil bath). The mixture was poured into saturated aqueous NH4Cl solution and extracted with
AcOEt. The AcOEt extracts were washed with brine, dried over Na2SO4, and evaporated to dryness.
Purification of the residue by column chromatography (hexane/AcOEt = 10) gave N-(2-pyridyl)-2-iso-
propylaniline (172 mg). Under N2 atmosphere, to NaH (60% assay, 65 mg, 1.6 mmol) in 1,4-dioxane
(2.0 mL) were added N-(2-pyridyl)-2-iso-propylaniline (172 mg, 0.8 mmol) and iodomethane (76 µL,
1.2 mmol), and then the mixture was stirred for 24 h at 80 °C (oil bath). The mixture was poured into
saturated aqueous NH4Cl solution and extracted with AcOEt. The AcOEt extracts were washed with
brine, dried over Na2SO4, and evaporated to dryness. Purification of the residue by column
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chromatography (AcOEt/MeOH = 4) gave 1 (159 mg, 70%). 1: colorless oil; IR (neat) 2963 cm-1; H
NMR (400 MHz, CDCl3) d: 8.21 (1H, dt, J = 5.0, 1.0 Hz), 7.42 (1H, dd, J = 7.8, 1.8 Hz), 7.34 (1H, td, J
= 7.6, 1.4 Hz), 7.22-7.28 (2H, m), 7.13 (1H, dd, J = 7.8, 1.4 Hz), 6.55 (1H, ddd, J = 7.8, 5.0, 0.9 Hz),
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6.02 (1H, d, J = 8.7 Hz), 3.38 (3H, s), 3.04 (1H, sept, J = 6.8 Hz), 1.15 (6H, brd); C{1H} NMR (100
MHz, CDCl3) d: 159.1, 147.6, 147.5, 143.5, 136.5, 128.8, 127.9, 127.6, 127.3, 112.0, 108.2, 38.3, 27.6,
24.2, 23.6; MS (m/z) 227 (MH+); HRMS (ESI) m/z: [M + H]+ calcd for C15H19N2 227.1548; found:
227.1560.
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N-Methyl-N-(2,6-dimethylpyridin-4-yl)-2-iso-propylaniline (2). Under N2 atmosphere, Pd(OAc)2 (9
mg, 0.04 mmol) and rac-BINAP (50 mg, 0.08 mmol) in toluene (0.5 mL) were stirred for 10 min at rt.
2-iso-Propylaniline (135 mg, 1.0 mmol) in toluene (1.0 mL), t-BuONa (144 mg, 1.5 mmol) and 4-
bromo-2,6-dimethylpyridine (186 mg, 1.0 mmol) in toluene (1.0 mL) were added to the reaction
mixture, and the mixture was stirred for 3 h at 110 °C (oil bath). The mixture was poured into saturated
aqueous NaHCO3 solution and extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over Na2SO4, and evaporated to dryness. Purification of the residue by column chromatography
(AcOEt/MeOH = 4) gave N-(2,6-dimethylpyridin-4-yl)-2-iso-propylaniline (240 mg). Under N2
atmosphere, to NaH (60% assay, 65 mg, 1.6 mmol) in DMF (2.0 mL) were added N-(2,6-
dimethylpyridin-4-yl)-2-iso-propylaniline (240 mg, 1.0 mmol) and iodomethane (75 µL, 1.2 mmol), and
then the mixture was stirred for 24 h at rt. The mixture was poured into saturated aqueous NaHCO3
solution and extracted with AcOEt. The AcOEt extracts were washed with brine, dried over Na2SO4,
and evaporated to dryness. Purification of the residue by column chromatography (AcOEt/MeOH = 4)
gave 2 (224 mg, 88%). 2: colorless oil; IR (neat) 2961 cm-1; 1H NMR (400 MHz, CDCl3) d: 7.42 (1H,
dd, J = 7.8, 1.8 Hz), 7.36 (1H, td, J = 7.4, 1.1 Hz), 7.27 (1H, td, J = 7.4, 1.6 Hz), 7.05 (1H, dd, J = 7.8,
0.9 Hz), 6.03 (2H, brs), 3.22 (3H, s), 2.89 (1H, sept, J = 6.8 Hz), 2.37 (6H, s), 1.14 (3H, d, J = 6.4 Hz),
1.10 (3H, d, J = 6.8 Hz); 13C{1H} NMR (100 MHz, CDCl3) d: 157.3, 152.2, 147.2, 143.3, 128.4, 128.1,
127.5, 127.3, 103.8, 39.2, 27.7, 24.5, 24.3, 23.4; MS (m/z) 277 (MNa+); HRMS (ESI) m/z: [M + Na]+
calcd for C17H22N2Na 277.1681; found, 277.1677.
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N-Methyl-N-(2-pyridinium)-2-iso-propylaniline methane sulfonate (1-H+). To 1 in CDCl3 was
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added 1.3 equivalent of MeSO3H and the H-NMR was measured at rt. 1-H+: H NMR (400 MHz,
CDCl3) d: 8.46 (1H, t, J = 5.5 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.45-7.51 (2H, m), 7.35 (1H, m), 7.10 (1H,
d, J = 7.8 Hz), 6.86 (1H, t, J = 6.4 Hz), 6.31 (1H, d, J = 8.7 Hz), 3.65 (3H, s), 2.92 (3H, s), 2.79 (1H,
sept, J = 6.8 Hz), 1.23 (3H, d, J = 6.9 Hz), 1.11 (3H, d, J = 6.9 Hz). 13C{1H} NMR (100 MHz, CDCl3)
d: 152.8, 146.0, 142.6, 139.3, 137.9, 130.3, 128.6, 128.3, 127.3, 112.6, 40.6, 39.3, 28.0, 24.1, 23.6.
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N-Methyl-N-(2,6-dimethylpyridinium-4-yl)-2-iso-propylaniline methane sulfonate (2-H+). To 1
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in CDCl3 was added 1.2 equivalent of MeSO3H and the H-NMR was measured at rt. H NMR (400
MHz, CDCl3) d: 7.44-7.50 (2H, m), 7.35 (1H, m), 7.04 (1H, dd, J = 7.3, 1.2 Hz), 6.55 (1H, s), 5.75 (1H,
s), 3.38 (3H, s), 3.22 (3H, s), 2.90 (3H, s), 2.73 (1H, m), 2.46 (3H, s), 1.22 (3H, d, J = 6.7 Hz), 1.11 (3H,
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d, J = 6.7 Hz). C{1H} NMR (100 MHz, CDCl3) d: 158.0, 152.7, 151.0, 145.8, 140.5, 129.9, 128.4,
128.1, 127.1, 106.3, 103.7, 40.3, 39.5, 28.0, 24.2, 23.6, 19.9, 19.4.
AUTHOR INFORMATION
Corresponding Authors
Osamu Kitagawa, E-mail: kitagawa@shibaura-it.ac.jp
Elsa Caytan, E-mail : elsa.caytan@univ-rennes1.fr
Christian Roussel, E-mail: christian.roussel@univ-amu.fr
ORCID
Osamu Kitagawa 0000-0001-7964-1879
Elsa Caytan
Christian Roussel 0000-0003-1377-7081
Daniel Farran 0000-0003-4687-7871
0000-0003-0490-3074
Nicolas Vanthuyne 0000-0003-2598-7940
Notes
The authors declare no competing financial interest.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Copies of H and C-NMR spectra, VT-NMR data and the determination of the rotational
barriers in 1, 2, 1-H+, 2-H+.
ACKNOWLEDGMENT
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This work was partly supported by JSPS KAKENNHI (C 17K08220).
REFERENCES
1. Typical papers on molecular rotors: (a) Iwamura, H.; Mislow, K. Stereochemical Consequences
of Dynamic Gearing. Acc. Chem. Res. 1988, 21, 175. (b) Kelly, T. R.; Silva, H.; Silva, R.
Unidirectional Rotary Motion in a Molecular System. Nature 1999, 401, 150. (c) Koumura, N.;
Zijlstra, R. W. J.; van Delden, R. A.; Harada, N.; Feringa, B. L. Light-driven Monodirectional
Molecular Rotor. Nature 1999, 401, 152. (d) Kottas, G. S.; Clarke, L. I.; Horinek, D.; Michl, J.
Artificial Molecular Rotors. Chem. Rev. 2005, 105, 1281. (e) Coskun, A.; Banaszak, M.;
Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A. Great Expectations: Can Artificial
Molecular Machines Deliver on Their Promise? Chem. Soc. Rev. 2012, 41, 19.
2. Typical papers on molecular brake: (a) Kelly, T. R.; Bowyer, M. C.; Bhaskar, K. V.; Bebbington,
D.; Garcia, A.; Lang, F.; Kim, M. H.; Jette, M. P. A Molecular Brake. J. Am. Chem. Soc. 1994,
116, 3657. (b) Takeuchi, M.; Imada, T.; Shinkai, S. A Strong Positive Allosteric Effect in the
Molecular Recognition of Dicarboxylic Acids by
a
Cerium(IV) Bis[tetrakis(4-
pyridyl)porphyrinate] Double Decker. Angew. Chem. Int. Ed. 1998, 37, 2096. (c) Jog, P.; Brown,
R.; Bates, D. A Redox-Mediated Molecular Brake:ꢀDynamic NMR Study of 2-[2-
(Methylthio)phenyl]isoindolin-1-one and S-Oxidized Counterparts. J. Org. Chem. 2003, 68,
8240. (d) Harrington, L. E.; Cahill, L. S.; McGlinchey, M. J. Toward an Organometallic
Molecular Brake with a Metal Foot Pedal:ꢀ Synthesis, Dynamic Behavior, and X-ray Crystal
Structure of [(9-Indenyl)triptycene]chromium Tricarbonyl. Organometallics, 2004, 12, 2884. (e)
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Yang, J.; Huang, Y.; Ho, J.; Sun, W.; Huang, H.; Lin, Y.; Huang, H.; Huang, S.; Lu, H.; Chao, I.
A Pentiptycene-Derived Light-Driven Molecular Brake. Org. Lett. 2008, 11, 2279. (f) Hirose,
K.; Ishibashi, K.; Shiba, H.; Doi, Y.; Tobe, Y. Highly Effective and Reversible Control of the
Rocking Rates of Rotaxanes by Changes to the Size of Stimulus-Responsive Ring Components.
Chem. Eur. J. 2008, 14, 5803. (g) Basheer, M. C.; Oka, Y.; Mathews, M.; Tamaoki, N. A Light-
Controlled Molecular Brake with Complete ON-OFF Rotation. Chem. Eur. J. 2010, 16, 3489.
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3. Iwasaki, Y.; Morisawa, R.; Yokojima, S.; Hasegawa, H.; Roussel, C.; Vanthuyne, N.; Caytan,
E.; Kitagawa, O. N-C Axially Chiral Anilines: Electronic Effect on Barrier to Rotation and A
Remote Proton Brake. Chem. Eur. J. 2018, 24, 4453.
4. Typical papers on molecular rotors based on the control of N-C bond rotation: (a) Dial, B. E.;
Rasberry, R. D.; Bullock, B. N.; Smith, M. D.; Pellechia, P. J.; Profeta, S, Jr.; Shimizu, K. D.
Guest-Accelerated Molecular Rotor. Org. Lett. 2011, 13, 244. (b) Dial, B. E.; Pellechia, P. J.;
Smith, M. D.; Shimizu, K. D. Proton Grease: An Acid Accelerated Molecular Rotor. J. Am.
Chem. Soc. 2012, 134, 3675. (c) Wu, Y.; Wang, G.; Li, Q.; Xiang, J.; Jiang, H.; Wang, Y. A
multistage rotational speed changing molecular rotor regulated by pH and metal cations. Nat.
Commun. 2018, 9, 1953.
5. Although the aromatic nucleophilic substitution of 2-iso-propylaniline with 4-bromo-pyridine
hydrochloride gave the desired N-(4-pyridyl)-2-iso-propylaniline, the chemical yield was poor.
6. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A Simple Catalytic Method for the
Conversion of Aryl Bromides to Arylamines. Angew. Chem. Int. Ed. Engl. 1995, 34, 1348. (b)
Hartwig, J. F.; Loue, J. Palladium-catalyzed synthesis of arylamines from aryl halides.
Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett. 1995, 36,
3609.
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7. (a) C. Wolf, Dynamic Stereochemistry of Chiral Compounds: Principles and Applications, RSC
Publishing: Cambridge, 2008. (b) Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S.
J. M. Controlling Axial Conformation in 2-Arylpyridines and 1-Arylisoquinolines: Application
to the Asymmetric Synthesis of QUINAP by Dynamic Thermodynamic Resolution. J. Am. Chem.
Soc. 2009, 131, 5331.
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8. Although the rotational brake around N-pyridinium bond in 1-H+ may also occur, it was difficult
to detect in the 2-pyridyl substrates having no equivalent hydrogens such as 4-pyridyl derivative
2-H+. On the other hand, in 4-aminophenyl derivative II, the non-equivalency of hydrogens on
4-aminophenyl ring was not observed through the addition of MeSO3H because of the low
+
rotational barrier around N-(4-NH3 Ph) bond.
9. The broadened signals of Me groups at low temperature may result from the physical state of the
solution.
10. One may augur that the oxidation or methylation at the pyridine nitrogen in 2 to yield the
corresponding N-oxide or N-methyl-pyridinium salt would also produce a strong deceleration of
the rotation rates. These chemical transformations which do not comply with the reversibility
requirement in molecular motor brake were not further considered.
11. A reviewer suggested that bevel gear bearing two orthogonal rotors is more appropriate than the
penny farthing bike as a mechanical analogy. This is right in terms of topology but the gear
analogy is somewhat misleading for our two blade molecular machine. The penny farthing bike
is another example in which two interdependent rotating systems with different rotation rates can
be simultaneously affected by a single brake.
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