Kinetic control of the direction of inclusion of nitroxide radicals into cyclodextrins

Article abstract of DOI:10.1039/c1ob05618b

N-benzyl-tert-butyl nitroxide derivatives substituted at the aromatic ring form host-guest inclusion complexes with β-and γ-cyclodextrin. They were employed as probes to assess substituent effects on the geometry of the complex and on the kinetics of this

Full text of DOI:10.1039/c1ob05618b

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PAPER
Kinetic control of the direction of inclusion of nitroxide radicals into
cyclodextrins†
Paola Franchi, Costanza Casati, Elisabetta Mezzina and Marco Lucarini*
Received 18th April 2011, Accepted 17th June 2011
DOI: 10.1039/c1ob05618b
N-benzyl-tert-butyl nitroxide derivatives substituted at the aromatic ring form host–guest inclusion
complexes with b-and g-cyclodextrin. They were employed as probes to assess substituent effects on the
geometry of the complex and on the kinetics of this complexation by combining EPR and 1H NMR
data.
and benzylic protons: a(N) = 15.74 G, a(2Hb) = 7.88 G, g =
Introduction
2.0058. Thus, in the presence of a suitable host system,10 EPR
spectra of this radical show signals clearly different for the free
and included species, and their ratio provides the value of the
equilibrium constant for the formation of the inclusion complex.
In addition, because the lifetimes of the two species are comparable
to the time scale of EPR spectroscopy, as suggested by the strong
dependence on the temperature of the spectral line width, this
technique permits us to obtain information on the kinetics of
association and dissociation of the inclusion complex.8
Control of the direction of incorporation of a guest into a host
and the relative molecular motion that takes place within the
complexes is of importance for the construction of molecular
machines.1–3 Pseudorotaxanes and rotaxanes are considered to
be a typical prototype of molecular machines bearing a rotor
and an axle in the molecule.4 When nonsymmetric macrocyclic
derivatives like calixarenes5 and cyclodextrins (CDs)6 are used
as three-dimensional rotor components, a significant increase
in structural complexity is possible because randomly oriented
structures deriving from the threading of suitable axles from the
two different rims of the host could be formed.
Harada and co-workers were able to report in detail the face-
selective threading of a CD molecule onto an axle compound
with one or two station moieties to give kinetically preferred
[2]- and [3]pseudorotaxanes.7 In particular, a methyl group at
the 2-position of a pyridinium group on the end cap of an axle
molecule consisting of polymethylene units was found to control
the rates of threading of a-CD. This was the first observation
that the terminal group of an axle molecule controls kinetically
the direction of faces of plural ring components in the rotaxane
structure. These results represented a significant step forward for
the construction of instructed chemical systems in which not only
the equilibrium states but also the dynamic behaviour could be
carefully controlled.
Kotake and Janzen have investigated in the late eighties the
thermodynamic factors governing the competitive inclusion of
two different groups inside a CD cavity by using spin probes
and EPR spectroscopy.11 However, to obtain pseudorotaxanes and
rotaxanes characterised by a univocal and programmable relative
orientation of their components, it is important to gain a deep un-
derstanding not only of the structural and thermodynamic factors
governing the inclusion processes but also of the kinetic aspects
of complexation. For this reason we decided to employ different
nitroxides deriving from BTBN (1b–6b, Scheme 1) having one
or two substituents on the aromatic ring and EPR spectroscopy
to obtain accurate rate constants for the formation/dissociation
of complexes between b-CD and g-CD. The selected nitroxides
were chosen because (i) they all maintain the favorable EPR
features found in the related benzyl tert-butyl nitroxide, (ii) they
can be obtained easily by oxidation of the corresponding amine
precursors 1a–6a, (iii) the presence of the aromatic substituents
governs both the degree and the geometry of complex formation
of CD with the guest molecules.
N-Benzyl-tert-butyl nitroxide (BTBN) has been largely used in
our previous work as a paramagnetic guest species for study-
ing cyclodextrin host systems.8–9 Due to the sensitivity of its
spectroscopic parameters (in water: a(N) = 16.69 G, a(2Hb) =
10.57 G, g = 2.0056)8 to the polarity of the environment, and
to conformational changes, after inclusion, BTBN shows large
variations of the hyperfine splitting constants at both nitrogen
Department of Organic Chemistry “A. Mangini”, University of Bologna, Via
San Giacomo 11, I-40126 Bologna, Italy. E-mail: marco.lucarini@unibo.it
† Electronic supplementary information (ESI) available: General
notes and 2D-ROESY spectra of host–guest complexes. See DOI:
10.1039/c1ob05618b
Scheme 1
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Table 1 EPR parametersa of nitroxides 1b–6b (1G = 0.1 mT) and rate
constantsb for their complexation by b-cyclodextrin in water at 328 K
To fully clarify the relationship between the geometry of
the CD assemblies and the complexation kinetics, EPR data
1
were correlated with H–1H NOE measurements carried out on
Nitroxide R1, R2 a(2Hb) a(N)
k
ass/M-1 s-1
k
diss/s-1
K
Eq/M-1
the complexes between CD’s and the structurally related amine
precursors 1a–6a.
1b
2b
3b
4b
5b
6b
H, H
10.19
7.58
16.56 1.5 ¥ 109
15.64
2.5 ¥ 106 600
3.8 ¥ 106 226
3.5 ¥ 106 140
2.4 ¥ 106 362
2.3 ¥ 106 269
3.8 ¥ 106 216
Me, H 13.01
10.81
Me, Me 17.93
16.71
Cl, H
Cl, Cl
Et, H
16.87 8.6 ¥ 108
16.10
Results and discussion
17.37 4.9 ¥ 108
16.61
EPR measurements
13.03
10.24
17.10
15.63
12.88
10.63
16.83 8.7 ¥ 108
15.96
The radical probes we used in this study belong to a family of ortho-
substituted benzyl-tert-butyl nitroxides (1b–6b, Scheme 1). They
were generated directly inside an EPR tube by oxidizing the parent
amine (0.5 mM) with the magnesium salt of monoperoxyphthalic
acid (0.5 mM) in the presence of variable amounts of CD. The
amine precursors were prepared by reacting tert-butylamine with
the appropriately substituted benzaldehyde followed by reduction
with NaBH4 (see Experimental section).
17.35 6.2 ¥ 108
16.79
16.88 8.2 ¥ 108
16.10
a The values given in bold type refer to the radical included in the b-CD
cavity. b Estimated uncertainty ca. 10%.
increasing the absolute concentration of CD, it was possible to
increase the amount of the included radical (see Fig. 1c) which in
most cases became the dominant species. In Table 1 are reported
the spectroscopic parameters for the included nitroxides.
The equilibrium constants (KEq) for the complex formation be-
tween nitroxides 1b–6b and the investigated CD were determined
from the values of the rate constants for association (kass) and
dissociation (kdiss) of the complex, obtained from the simulation
of the exchange-broadened EPR spectra, by using well-established
procedures based on the density matrix theory8 and assuming a
two-jump model as illustrated in Scheme 2.
Good EPR spectra of nitroxides 1b–6b in water were obtained
in all cases by oxidation of the corresponding amines both at
298 K and 328 K. As an example, in Fig. 1a it is reported the
spectrum obtained by oxidizing amine 4a in water at 328 K. All
spectra were easily interpreted on the basis of the coupling of
the unpaired electron with nitrogen, and with the two benzylic
protons (see Table 1). When the EPR spectra of radicals 1b–6b were
recorded in the presence of CD, additional signals were observed
assigned to the radical included in the cavity of cyclodextrin, in
equilibrium with the free nitroxide.‡ As an example, Fig. 1b reports
the spectrum of 4b recorded in the presence of 10 mM b-CD. By
Scheme 2
EPR kinetic data
As expected, the kinetic data in Table 1 show that the rate constants
for the inclusion of the guest radical by b-CD, kass, depend both
on the nature and the number of the substituents at the 2 and 6
positions of the aromatic ring. With the mono- (2b, 4b and 6b)
and di-substituted derivatives (3b and 5b), a reduction of ca. two
and three times, respectively, in the value of the association rate,
kass, is observed compared to the unsubstituted BTBN.
Fig. 1 EPR spectra at 328 K of nitroxide 4b in water (a) and in the
presence of b-CD 10 mM (b) and 17 mM (c). Theoretical simulations are
reported as dotted lines.
The relatively small variation of kass observed is similar to
that reported by Nau and coworkers during the investigation
on the substituent effects on host–guest complexation of bicyclic
azoalkanes by b-CD.12
The smaller values of the association observed in the presence
of substituted radicals indicate the presence of a larger steric
hindrance between the aromatic substituents and the rim of the
b-CD. This hypothesis is corroborated by the observation of less
marked differences in the values of kass with g-CD. Actually, in
the presence of the larger member of the cyclodextrin family,
where steric effects on the inclusion process are expected to be less
‡ Recently, the first example of inclusion complexes between a CD
derivative and aromatic guests possessing no charge and no acidic hydrogen
in nonpolar solvents has been reported (see reference 13). In particular, it
was shown that chlorinated benzenes can be included inside the cavity
of heptakis(6-O-tert-butyldimethylsilyl)-b-cyclodextrin (TBDMS-b-CD)
in nonpolar solvents like benzene or cyclohexane. Based on this, we
checked by EPR if also chlorinated nitroxides such as 4b, 5b and (2,4,5-
trichloro)-1-benzyl-tert-butyl nitroxide could form inclusion complexes
with TBDMS-b-CD. Unfortunately, we did not have any evidence by EPR
of the formation of inclusion complexes both in benzene and cyclohexane.
This result suggests that the behaviour observed by Kida et al. cannot be
generalised to chlorinated benzenes having other substituents.
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Table 2 EPR parametersa of nitroxides 1b–6b (1G = 0.1 mT) and rate
constantsb for their complexation by g-cyclodextrin in water at 295 K
ROESY spectra gave a clear indication on the inclusion direction
of the guest and the results are discussed below (see also Scheme 3).
Nitroxide R1, R2 a(2Hb) a(N)
k
ass/M-1 s-1
k
diss/s-1
K
Eq/M-1
1b
2b
3b
4b
5b
6b
H, H
10.63
8.02
16.71 3.8 ¥ 108
15.97
7.6 ¥ 106 50.7
5.3 ¥ 106 50.9
7.0 ¥ 106 44.2
4.1 ¥ 106 70.7
3.2 ¥ 106 84.4
3.0 ¥ 106 100
Me, H 13.63
10.91
Me, Me 18.37
16.41
Cl, H
Cl, Cl
Et, H
16.97 2.7 ¥ 108
16.24
17.47 3.1 ¥ 108
16.84
13.75
10.68
17.52
15.66
13.43
10.90
16.98 2.9 ¥ 108
16.21
17.50 2.7 ¥ 108
16.80
Scheme 3
17.00 3.0 ¥ 108
16.39
The ROESY spectrum of non-substituted benzyl tert-
butylamine 1a in the presence of b-CD shows significant interac-
tions of the tert-butyl protons of the guest molecule with the inner
H3 (strong) and H5 (medium) cyclodextrin protons. The spectrum
shows also cross-peaks correlating aromatic protons only with
overlapped H5/H6 (medium) protons located at the smaller edge
of the macrocyclic host, while correlations of the phenyl peaks
with the CD inner H3 signal were never detected (see the ESI†).
Concerning the position of the benzyl protons, the interpreta-
tion of the NMR spectra of the inclusion complexes was difficult to
achieve, due to its close chemical shift value with the cyclodextrin
H3–H6 proton signals (3.70–4.00 ppm). In this case the detection
of distinct cross-peaks was difficult due to overlapping and the
same behavior was observed for all the amines analyzed in this
study.
Anyway, these results suggest that inclusion of 1a into the CD
cavity occurs from the phenyl portion of BTBA which is located
close to the primary (i.e. the smaller) CD rim, and the tert-butyl
group of the guest is accommodated near the secondary (i.e. the
larger) side of the host. This geometry agrees well with previous
results obtained by us in a study of the solution structure of the
complex of the same amine with 2,6-O-dimethylated b-CD.14
The opposite conclusions were achieved when analyzing the
complex geometry of 1a included in the larger g-cyclodextrin
cavity. In this case, 1H–1H ROESY interactions of aromatic
protons with H3 are the only connections detected, while tert-
butyl protons are deeply included in the macrocycle revealing not
only cross-peaks with inner H3 and H5, but also a weak interaction
with H6 protons surrounding the minor rim of the host (see the
ESI† and Scheme 3). From these experimental data we deduced
that the phenyl ring of the amine is near the secondary edge of
g-CD in a reverse geometry with respect to the smaller b-CD.
ROESY spectra were also recorded for solutions containing
amine 2a and b-CD in 0.2 : 1.0 host : guest stoichiometric ratio.
Cross-peaks were detected between tert-butyl protons and the H3,
H5, and H6 protons of CD (see Fig. 2). In this spectrum the
splitting of CD H5 and H6 signals allowed us to observe distinct
cross peaks for each proton which were stronger for H5 than for
minor rim H6, and an intense interaction was recorded also with
the inner H3 of the host (square in plot b, Fig. 2).
a The values given in bold type refer to the radical included in the g-CD
cavity. b Estimated uncertainty ca. 10%.
important, rate constants for the association kass are very similar
for all the investigated nitroxides (see Table 2).
The dissociation rate constants (kdiss) define the lifetimes of
the guests in the CD cavity and cannot be easily related to the
bulkiness of the aromatic substituents. While with alkyl groups the
larger values of kdiss are consistent with the larger steric hindrance
between the guest and the internal cavity of b-CD, with both
chlorine substituted nitroxides 4b and 5b, kdiss is very similar to
the value measured for the unsubstituted derivative. In this case
the increased steric hindrance of the guest due to the presence of
a second chlorine atom is balanced by the increased dipole–dipole
interactions between the host cavity and the guest molecule which
are known to be important in stabilizing the complex with guests
containing chlorine atoms.12,13
This interpretation was confirmed by measuring kdiss, in the
presence of g-CD. In this case steric effects are less important and
kdiss for 4b and 5b are smaller with respect to the value measured
with BTBN due to the favourable dipole–dipole interaction
present in the former cases.
Geometry of the complexes
In principle, two modes of accommodation in the larger rim are
possible with nitroxides 1b–6b: either from the tert-butyl side or
from the phenyl side. By using NMR, we were able in the past
to demonstrate that in BTBN the inclusion is occurring from the
benzyl side.14
For the substituted probes 2b–6b, however, the increased
bulkiness of the benzyl substituents could result in a change in the
geometry of the complex. In order to get insight into the geometry
of the inclusion complexes in liquid phase between the investigated
paramagnetic compounds and cyclodextrins, we decided to repeat
1H NMR experiments with the diamagnetic related precursors of
the nitroxides, i.e. amines 1a–3a and 6a, in the absence and in the
presence of b-CD and g-CD. The choice of amine precursor was
determined by the difficulties associated with the characterization
of paramagnetic species through NMR.
More interestingly, the aromatic protons of amine 2a displayed
an interaction only with the H3 signal (plot a, Fig. 2) in contrast to
what was observed in the case of 1a. Finally, cross peaks between
the signal of the ortho-methyl substituent and CD H5 and H6
protons were not observed while a weak interaction with H3 was
detected.
The spectra were measured for D2O samples containing 5%
CD3OD to ensure complete dissolution of N-benzyl-tert-butyl
amine (BTBA) derivatives. 2D ROESY experiments were carried
out in solutions of amines containing from 0.2 to equimolar
amounts of b-CD and g-CD, with mixing times 300 ms. Analysis of
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ROESY spectra were measured for samples containing amine 6a
treated with 40–80% stoichiometric amounts of b-CD.
The presence of cross peaks (see the ESI†) connecting the
methylene ring-substituents (of the ethyl group) of 6a with H3
b-CD protons only, and which were not observed with H5 and
H6, together with interactions of the tert-butyl portion with H3
(strong), H5 (medium) and H6 (weak), and connection of phenyl
ring protons with H3, indicate that the inclusion of the amine into
the CD occurs from the tert-butyl side.
By combining EPR and NMR data it was possible to conclude
that the smaller association rate constants observed with 2b–3b
and 6b described the inclusion process of the probe by the tert-
butyl side.
Fig. 2 Portion of the ROESY spectra of a 0.5 mM solution of 2a (right,
X range from 1.00 to 1.50 ppm, Y range from 3.60 to 4.07 ppm; left, X
range from 7.14 to 7.41 ppm, Y range from 3.70 to 3.97 ppm) containing
0.1 mM b-CD in D2O at 298 K. The dotted line square evidences in the
plot a the cross peak connecting the phenyl ring protons of 2a with H3 CD
protons only, which was not observed with H5 and H6. The square in the
plot b highlights the deep inclusion of the tert-butyl portion of the amine
into the CD.
Nitroxide conformations
Information on the preferred conformations adopted by the
different radicals in the various environments can be obtained
from the magnitude of a(Hb). The value of the hyperfine splitting
constant for b-protons in alkyl nitroxides depends on the spin
population in the 2pp-orbital of nitrogen (rpN) and on the dihedral
angle (J) between the symmetry axis of this orbital and the N–C–
Hb plane (eqn (1)).15
The analysis of these results reveals an opposite direction of
inclusion of the ortho-methyl derivative 2a with respect to the
non-substituted amine 1a. Due to the increased bulkiness of
the aromatic ring, the monosubstituted BTBA is included from
the tert-butyl side, which is located at the smaller edge of the
host, while the phenyl ring resides near the secondary rim of the
macrocycle.
Similar spectral results are obtained on investigating the be-
haviour of 2a in the presence of g-CD. The spectra (see the
ESI†) recorded for solutions of the amine containing increasing
amounts of the macrocycle reveal the same interactions for the
tert-butyl group (with CD H3/H5/H6) already observed in the
inclusion complex with b-CD. Conversely, the spectra do not
report intermolecular correlation for the phenyl ring and the inner
protons of the host, indicating a larger freedom of the aromatic
ring in the complex, presumably due to the larger size of the cavity.
ROESY spectra of the sample containing amine 3a and b-CD
in an equimolar stoichiometric ratio show clear interactions both
for tert-butyl and ortho-dimethyl substituents (see the ESI†). In
particular the former is correlating with the inner H3/H5 and
the primary rim (H6) protons and the latter show connections
only with H3. In contrast, no intermolecular cross-peak has been
recorded for phenyl ring.
Together these results suggest that the 2,6-disubstituted benzyl
amine shows a mode of inclusion into b-CD similar to what was
observed for monomethylated 2a, however the lack of interactions
of the aromatic proton with CD internal protons suggest a looser
complex than that with 2a in which the tert-butyl part of the amine
is located close to the primary CD rim and the phenyl group of the
guest exposed to the solvent from the secondary side of the host.
NOE considerations regarding the complex of 3a with the larger
cavity g-CD are in line with the previous results exposed for
the monosubstituted benzyl derivative (2a), that is less intense
interactions with inner CD protons, but the same direction of
inclusion (tert-butyl group inside the minor rim). Also in this case
intermolecular NOEs are not observed for the aromatic proton of
the amine.
p
a(Hb) = rN (AN + BNꢀcos2 Jꢁ)
(1)
The constant AN is small and usually neglected, while BN is ca. 59
G.16 By using this value and by considering the splitting observed
at the methyl protons in methyl benzyl nitroxide (13.34 G) where
ꢀcos2 Jꢁ = 0.5 for symmetry reasons an approximate value of 0.45
for rp can be obtained.8
N
The knowledge of the approximate value of rp makes it
N
possible to predict the preferred conformations adopted by the
radicals both in solution and included inside the CD cavity. In
conformation A (Scheme 4), where the dihedral angle between the
Ar–C and N–O bonds (a) is zero and (J) is for both hydrogens 30◦
the value of a(H) is expected to be ca. 19.9 G. In conformation C,
a(Hb) values equal to 19.9 G for one proton and a(Hb) = 0 G for
the other proton are expected. However, a fast exchange between
this conformation and the enantiomeric conformation C* with
a = -120◦ would make both hydrogens equivalent so that a value
of ca. 10 G for both protons would be expected. In conformation
B, a(Hb) is expected to be about 6.0 G for both hydrogens.17 If we
restrict the analysis to the symmetric derivatives, the experimental
values of a(Hb) reported in Table 1 indicate that in water solution
the minimum energy conformation of 1b should be close to C
while in nitroxides 3b and 5b the preferred conformation adopted
should be very similar to A.
Scheme 4
An investigation on size increase of the guest ortho-substituent
in the control of the inclusion direction is also described. Some
When the probe 1b is included inside the b-CD cavity, the
radical is experiencing a less polar environment with respect to
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water. This gives rise to a decrease of rp as indicated by the
With 1b, calculations indicated that conformations close to the
geometry of C are the most stable as suggested by analysis of
a(Hb) splitting. Conformer B lies very close to conformer C, while
conformer A is less stable than the conformer C by 2.0 kcal mol-1.
Analysis of the potential energy vs. dihedral angle plots (see Fig. 3)
showed that the largest energy expenditures (5.5 kcal mol-1) are
required for the transformation between the two enantiomeric
conformations C having a = 120◦ and by passing with the phenyl
and tert-butyl eclipsed.
On the contrary, with 3b and 5b calculations indicated that
a conformation close to the geometry of A represents the most
stable conformer. In this case conformer C is less stable than
the conformers A by ca. 1.1 and 1.7 kcal mol-1 in 3b and 5b,
respectively. Analysis of the potential energy vs. dihedral angle
plots (see Fig. 3) showed that a very large amount of energy (ca.
4 kcal mol-1) is required for the A → C transformation. This
confirms that 3b and 5b are indeed characterized by a reduced
conformational freedom around the ∑ON–CH2CAr bond.
N
reduction observed both in the value of a(N) and a(Hb). However,
the inclusion of 1b leads to a larger decrease in the value a(Hb)
(7.58 G) than expected based on eqn (1) (77% of the expected
value of 9.62 G). This clearly suggests that a change in the
conformation adopted by the radical is observed upon inclusion in
the CD cavity and that the energy barrier between the two different
conformations must be very low. The decrease in the hydrogen
splitting implies that inside the CD cavity the conformation B in
which the phenyl group is eclipsed by the N-2pp orbital is more
important than in solution.
On the contrary, disubstituted derivatives 3b and 5b show a value
of a(Hb) (16.71 G and 15.63 G) much closer to that expected on
the simple reduction of rp (97% and 95% of the expected values,
N
respectively), this being an indication that the inclusion is not
able to change drastically the occupancy of the minimum energy
conformation. This behaviour is consistent with the assumption
that the inclusion is occurring from the tert-butyl side, which is
expected to leave the conformation around the benzylic bond
similar to the one adopted in water.
Conclusions
In principle, the reduced differences in the values of a(Hb) for
the free and included species in 3b and 5b with respect to BTBN
can also be related to a decrease in the conformational freedom
Kinetic, and structural aspects of complexation by cyclodextrins
play an essential role in the understanding of their functions and
for the development of prospective applications. The solution
structures are intimately related to molecular recognition, and the
specific location of functional groups inthe CD cavity, in particular
in solution, may be a prerequisite for the construction of instructed
chemical systems in which not only the equilibrium states but also
the dynamic behaviour could be carefully controlled. By using
specifically designed EPR spin probes and their corresponding
diamagnetic precursors, we could distinguish different geometries
of inclusion complexes. We also provided herein a data set for
substituent effects on EPR parameters, association rate constants
for complexation of nitroxides 2b–6b by b- and g-CD and the
solution structures of the resulting complexes. Work to extend this
approach to other supramolecular systems is in progress.
∑
around the ON–CH2CAr bond deriving from an increase in the
energy barrier for the bond rotation. Actually, in the presence of
g-CD, which forms in all cases host–guest complexes with the same
geometry (vide supra), the inclusion of 1b leads to a larger decrease
in the value a(Hb) (78% of the expected value) while with 3b and
5b the included radicals have a(Hb) close to those expected from
eqn (1) (92% and 95%, respectively).
In order to rationalize the result obtained in the presence of
g-CD, we performed a theoretical calculation of the rotational
∑
barrier of the ON–CH2CAr bond in the derivatives 1b, 3b and
5b. The barriers to internal rotation were calculated using the
B3LYP/6-31+G(d,p) method.18 The dependences of the potential
energy on the dihedral angles (Fig. 3) were determined by scanning
the dihedral angle from 0 to 360◦ with an increment of 20◦ and
geometry optimization in each step. At each energy minimum, the
molecular geometry was fully optimized.
Experimental
General procedure for the preparation of amines 2a–6a
A toluene solution (150 ml) of tert-butyl-amine (15 mmols) and
the appropriate substituted benzaldehyde (15 mmols), was stirred
and heated under reflux for 10 h. During the reaction water was
removed by a Dean–Stark apparatus. The solution was cooled and
evaporated under reduced pressure to afford the corresponding
imine (yield 90–95%). The imine (14 mmols) was then dissolved
in a solution 1 : 1 of THF–methanol (150 ml), and stirred at
room temperature for 2 h in the presence of NaBH4 (14 mmols).
Another portion of NaBH4 was then added to the reaction mixture
(14 mmols) and the solution was stirred further for 16 h. The
solution was treated with HCl 6 N (150 ml) and the solvent
was removed by evaporation under reduced pressure. The residue
was treated with aqueous NaOH 5 N (100 ml) and extracted
with CH2Cl2 (100 ml ¥ 3). The organic phase was washed with
water (100 ml), before being dried (Na2SO4) and evaporated
under reduced pressure. The product was purified by column
chromatography (eluent petroleum ether–ethyl acetate 6/4, v/v)
to give the amine (yield 80–85%).
Fig. 3 Relative energies as a function of the ∑ON–CH2CAr dihedral angle
(a) in the nitroxides 1b, 3b and 5b.
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2a. Elemental analysis for C12H19N Calc.: C, 81.30; H, 10.80;
N, 7.90; Found C, 81.35; H, 10.72; N, 7.94; IR nmax/cm-1 3319
(NH), 748(CAr-H); 1H-NMR (300 MHz, CDCl3) d 7.32–7.28 (m,
1H), 7.17–7.10 (m, 3H), 3.7 (s, 2H), 2.38 (s, 3H), 1.20 (s, 9H);
GC-MS (m/z): 177 (M+, 10) 162 (M+-15, 33), 105 (M+-72, 100);
EPR parameters of the corresponding nitroxide 2b: see Table 1.
Chem., Int. Ed., 2000, 39, 3453; T. Yamagishi, A. Kawahara, J. Kita, M.
Hoshima, A. Umehara, S. Ishida and Y. Nakamoto, Macromolecules,
2001, 34, 6565; A Credi, S. Dumas, S. Silvi, M. Venturi, A. Arduini, A.
Pochini and A. Secchi, J. Org. Chem., 2004, 69, 5881; A. Arduini, F.
Ciesa, M. Fragassi, A. Pochini and A. Secchi, Angew. Chem., Int. Ed.,
2005, 44, 278; A. Arduini, R. Bussolati, A. Credi, A. Pochini, A. Secchi,
S. Silvi and M. Venturi, Tetrahedron, 2008, 64, 8279; A. Arduini, R.
Bussolati, A. Credi, G. Faimani, S. Garaude`e, A. Pochini, A. Secchi,
M. Semeraro, S. Silvi and M. Venturi, Chem.–Eur. J., 2009, 15, 3230.
6 J. Pozuelo, F. Mendicuti and W. L. Mattice, Macromolecules, 1997,
30, 3685; J. E. H. Buston, J. R. Young and H. L. Anderson, Chem.
Commun., 2000, 905; K. Miyake, S. Yasuda, A. Harada, J. Sumaoka,
M. Komiyama and H. Shigekawa, J. Am. Chem. Soc., 2003, 125, 5080;
J. W. Park and H. Song, Org. Lett., 2004, 26, 4869.
7 T. Oshikiri, Y. Takashima, H. Yamaguchi and A. Harada, J. Am. Chem.
Soc., 2005, 127, 12186; T. Oshikiri, Y. Takashima, H. Yamaguchi and
A. Harada, Chem.–Eur. J., 2007, 13, 7091.
8 M. Lucarini, B. Luppi, G. F. Pedulli and B. P. Roberts, Chem.–Eur. J.,
1999, 5, 2048.
9 P. Franchi, M. Lucarini, E. Mezzina and G. F. Pedulli, J. Am. Chem.
Soc., 2004, 126, 4343; P Franchi, G. F. Pedulli and M. Lucarini, J. Phys.
Chem. A, 2008, 112, 8706; E. Mileo, P. Franchi, R. Gotti, C. Bendazzoli,
E. Mezzina and M. Lucarini, Chem. Commun., 2008, 1311.
10 M. Lucarini, P. Franchi, G. F. Pedulli, C. Gentilini, S. Polizzi, P. Pengo,
P. Scrimin and L. Pasquato, J. Am. Chem. Soc., 2005, 127, 16384.
11 (a) Y. Kotake and E. G. Janzen, J. Am. Chem. Soc., 1988, 110, 3699; Y
Kotake and E. G. Janzen, Chem. Phys. Lett., 1988, 150, 199; Y. Kotake
and E. G. Janzen, Chem. Express, 1988, 3, 715; Y. Kotake and E. G.
Janzen, J. Am. Chem. Soc., 1989, 111, 2066; Y. Kotake and E. G. Janzen,
J. Am. Chem. Soc., 1989, 111, 5138; Y. Kotake and E. G. Janzen, Free
Rad. Res. Comms., 1990, 10, 103.
3a. Elemental analysis for C13H21N Calc.: C, 81.61; H, 11.06;
N, 7.32; Found C, 81.70; H, 11.02; N, 7.42; IR nmax/cm-1 3322
(NH), 770 (CAr-H); 1H-NMR (300 MHz, CDCl3) d 7.12–6.93 (m,
3H), 3.74 (s, 2H), 2.41 (s, 6H), 1.19 (s, 9H); GC-MS (m/z): 191
(M+, 10) 176 (M+-15, 25), 119 (M+-72, 100); EPR parameters of
the corresponding nitroxide 3b: see Table 1.
4a. Elemental analysis for C11H16ClN Calc.: C, 66.83; H, 8.16;
Cl, 17.93; N, 7.08; Found C, 66.91; H, 8.22; Cl, 17.68; N, 7.04;
1
IR nmax/cm-1 3313 (NH), 1055 (CAr-Cl), 758 (CAr-H); H NMR
(300 MHz, CDCl3) d 7.46 (dd, 1H, J = 7.4 and 1.5 Hz), 7.31
(dd, 1H, J = 7.4 and 1.5 Hz), 7.20–7.15 (m, 2H), 3.81 (s, 2H),
1.19 (s, 9H); GC-MS (m/z): 197 (M+, 5) 182 (M+-15, 60), 125
(M+-72, 100); EPR parameters of the corresponding nitroxide 4b:
see Table 1.
5a. Elemental analysis for C11H15Cl2N Calc.: C, 56.91; H,
6.51; Cl, 30.54; N, 6.03; Found C, 56.55; H, 6.62; Cl, 30.25; N,
1
5.94; IR nmax/cm-1 3321 (NH), 1058 (CAr-Cl), 768 (CAr-H); H-
12 X. Zhang, G. Gramlich, X. Wang and W. M. Nau, J. Am. Chem. Soc.,
2002, 124, 254.
NMR (300 MHz, CDCl3) d 7.28 (d, 2H, J = 8.4 Hz), 7.11 (t, 1H,
J = 8.4 Hz), 4.00 (s, 2H), 1.18 (s, 9H); GC-MS (m/z): 231 (M+,
2) 216 (M+-15, 80), 159 (M+-72, 100); EPR parameters of the
corresponding nitroxide 5b: see Table 1.
13 T. Kida, Y. Fujino, K. Miyawaki, E. Kato and M. Akashi, Org. Lett.,
2009, 11, 5282.
14 M. Lucarini, E. Mezzina and G. F. Pedulli, Eur. J. Org. Chem., 2000,
3927.
6a. Elemental analysis for C13H21N Calc.: C, 81.61; H, 11.06;
N, 7.32; Found C, 81.72; H, 11.01; N, 7.26; IR nmax/cm-1 3319
15 C. Heller and H. M. McConnell, J. Chem. Phys., 1960, 32,
1535.
16 H. G. Aurich, “The Chemistry of Amino, Nitroso, Nitro Compounds and
of their Derivatives”, (Ed.: S. Patai), Wiley, Chichester, 1982, p. 565.
17 Of course, it must be borne in mind that predictions based on eqn (1)
will be only semi-quantitative and that the conformations indicated are
averages over the populated torsional states.
18 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb,J. R. Cheeseman, J. A. Montgomery, T. Vreven, K. N.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.
Nakatsuji, M. Hada, M. Ehara, K. Topyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Makajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X.
Li, J. E. Know, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austlin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.
Cliffors, J. Cioslowski, B. B. Stefanov,G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi,R. L. Martin,D. J. Fox, T. Keith, M. A. Al-Latham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03, Revision
B05, Gaussian, Inc., Pittsburgh, 2003.
1
(NH), 758 (CAr-H); H-NMR (300 MHz, CDCl3) d = 7.34–7.32
(m, 1H), 7.21–7.15 (m, 3H), 3.74 (s, 2H), 2.74 (q, 2H, J = 7.5 Hz),
1.26 (t, 3H, J = 7.5 Hz), 1.20 (s, 9H); GC-MS (m/z): 191 (M+,
10) 176 (M+-15, 45), 119 (M+-72, 100); EPR parameters of the
corresponding nitroxide 6b: see Table 1.
Notes and references
1 A. Harada, Acc. Chem. Res., 2001, 34, 456.
2 H.-R. Tseng, S. A. Vignon and J. F. Stoddart, Angew. Chem., Int. Ed.,
2003, 42, 1491.
3 W. H. Chen, M. Fukudome, D. Q. Yuan, T. Fujioka, K. Mihashi and
K. Fujita, Chem. Commun., 2000, 541; T. Felder and C. A. Schalley,
Angew. Chem., Int. Ed., 2003, 42, 2258; H. Onagi, C. J. Blake, C. J.
Easton and S. F. Lincoln, Chem.–Eur. J., 2003, 9, 5978.
4 Themed issue Jean-Pierre Sauvage, Chem. Soc. Rev., 2009, 38, pp. 1509–
1824.
5 Z. Zhong, A. Ikeda and S. Shinkai, J. Am. Chem. Soc., 1999, 121, 11906;
A. Arduini, R. Ferdani, A. Pochini, A. Secchi and A. Ugozzoli, Angew.
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