Atropisomers of arylmaleimides: Stereodynamics and absolute configuration

Article abstract of DOI:10.1021/jo400200v

4-Aryl-3-bromo-N-benzylmaleimides and 3,4-biaryl-N-benzylmaleimides have been synthesized by a modified Suzuki cross-coupling reaction from 3,4-dibromo-N-benzylmaleimide. The conformational studies by dynamic NMR and DFT calculations showed that the interconversion barrier between the two available skewed conformations is under steric control. When the aryl group was a 2-methylnaphthyl, thermally stable atropisomers were isolated by enantioselective HPLC and their absolute configurations were assigned by TD-DFT simulations of the ECD spectra.

Full text of DOI:10.1021/jo400200v

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Article
Atropisomers of arylmaleimides: Stereodynamics and Absolute Configuration
Martina Ambrogi, Alessia Ciogli, Michele Mancinelli, Silvia Ranieri, and Andrea Mazzanti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400200v • Publication Date (Web): 25 Mar 2013
Downloaded from http://pubs.acs.org on March 26, 2013
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Introduction
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Restricted rotation around bonds in molecules can result in the formation of atropoisomers.1
Provided that the necessary geometric requirements are met, atropoisomers might be chiral and
configurationally stable. The conformational properties of atropisomeric molecules have attracted
interest in recent years due to their applications to drug discovery,2 and the synthesis of enantiopure
atropisomers of natural products is also an open research field.3 Many effective organocatalysts are
based on an atropisomeric scaffold such as BINOL,4 and atropisomeric phosphines are well known as
chiral ligands in metal catalysis.5 In the vast majority of cases, atropisomeric molecules have a planar
framework with one or more substituents linked in key sites. These substituents, which are often
variously decorated aromatic groups, adopt tilted conformations relative to the molecular plane, thus
generating a stereogenic axis. Depending on the hindrance of the substituents and on the geometry of
the planar framework, the resulting conformational enantiomers can be either stereolabile or
configurationally stable (atropisomers6). The corresponding barriers of interconversion can be usually
determined by means of variableꢀtemperature NMR spectroscopy,7 NMR kinetic methods (EXSY and
standard kinetic measurements), dynamic HPLC and GC.8,9
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3,4ꢀdisubstituted maleimides exhibit biological properties including antibacterial, antiviral
activity and they are potent inhibitors of glycogen synthase kinaseꢀ3 (GSKꢀ3).10 Substituted
maleimides which have extended conjugation have been considered as light emitting diodes (OLED),11
and fluorescence devices.12 Nelson et al13 found that a pair of indolyl substituents do not allow to
obtain maleimidic atropisomers, and they were able to generate stable atropisomers only by
constraining the two heterocyclic rings into a macrocycle. Based on previous experiences,14 in the
present work it was exploited the ability of the maleimide scaffold to generate stable atropisomers
when two unsymmetrically substituted aryl rings are bound to the 3,4ꢀposition. Their separation by
means of HPLC and the determination of the absolute configuration will be also pursued.
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Results and discussion
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To determine the steric requirements necessary to obtain stable atropisomers of bisꢀ
arylmaleimides, and to keep a reactive site in the molecule (compounds 3), a set of orthoꢀaryl
substituted boronic acids were reacted with 3,4ꢀdibromobenzylmaleimide (see Scheme 1). Different
synthetic approaches have been reported for the preparation of 3,4ꢀdisubstituted maleimides, most of
which based on metalꢀcatalysed crossꢀcoupling reactions of 3,4ꢀdihalomaleimides.15 A modified Suzuki
coupling, under milder conditions, was found to be the most effective approach to obtain the
compounds reported in Scheme 1. Anhydrous conditions were required to preserve the imidic moiety
when highly hindered boronic acids were used and dry THF was used together with solid Cs2CO3 under
inert atmosphere (see the experimental section).
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Scheme 1. Preparation of compounds 3aꢀ3f and 4aꢀ4f
Ar = 2ꢀmethylphenyl (a), 2ꢀethylphenyl (b), 2,3ꢀdimethylphenyl (c), 2ꢀisopropylphenyl (d),
1ꢀnaphthyl (e), 2ꢀmethylnaphthyl (f).
BisꢀAryl Maleimides
When equal aryl substituents, lacking a local C2ꢀsymmetry axis, are bonded in appropriate
positions to planar frameworks (such as benzene,16 naphthalene,17 phenanthrene,18 anthracene,19
acenaphthene,20 acenaphthylene,21 biphenylene22), configurationally stable isomers or stereolabile
syn/anti conformers are originated, depending on the extent of the steric hindrance. The existence of
syn/anti stereoisomers is the consequence of the planes of the two aryl substituents being twisted with
respect to the planar scaffold (see Scheme 2).
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Scheme 2. Steric and π barriers in arylꢀaryl compounds.
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In these situations the substituent on the aryl ring can stay either on the same (syn) or on the
opposite side (anti) with respect to the other one. Their interconversion, corresponding to a 180°
rotation, requires the passage through a transition state where one ring is coplanar with the scaffold
(Scheme 2, steric barrier8). It was also pointed out that the twisted disposition of the two aryl rings
would allow the syn form to originate a pair of enantiomers, that interconvert through a transition state
where the rings are nearly orthogonal to the scaffold (Scheme 2, πꢀbarrier8): this process corresponds to
a torsion around the bond connecting the Aryl group to the scaffold (also called flipping process) of
approximately 90°. In the case of the anti form, on the other hand, this nearly 90° torsion would create
two conformational diastereoisomers with different stability, identified as antiꢀin and antiꢀout.9 Each of
these conformers exists as a pair of enantiomers, but their enantiomerization requires the passage
through the syn isomer, i.e. the 180° rotation involving the steric barrier (Scheme 2). However, the πꢀ
barrier is usually very low, and its value decreases with the increasing of the steric barrier. Indeed this
feature was observed by Dynamic NMR only in one case on a metaꢀsubstituted bisꢀaryl biphenylene.14a
In the case of maleimides, DFT computational studies23 support the existence of different syn
and anti conformers due to the skewed disposition of the two aryl rings. However, the aryl rings are not
perpendicular to the maleimide plain, thus two diastereoisomeric conformations are available for the
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anti form whereas the syn yields a fastꢀexchanging enantiomeric pair (see Scheme 3).
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Scheme 3. Stereodynamic Network of 3,4ꢀbisarylmaleimides. Blue: Aryl Rings; Cyan: Maleimide
ring
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To theoretically analyse the stereodynamic pathways, we performed DFT optimization of both
ground states and of the available transition states at the B3LYP/6ꢀ31G(d) level of theory. (See Table
1). The calculated energy value for the πꢀbarrier of the less hindered compound 4a suggested a value as
low as 3.8 kcal/mol, thus for the following conformational analysis the syn and anti conformations can
be considered as the average of the limiting structures.
Table 1. DFT computed energies of 3,4ꢀbisarylꢀNꢀbenzylmaleimides 4aꢀ4f. The last two columns
report experimental energy barriers (∆G≠ in kcal/mol) and experimental syn/anti ratios.
Entry
Exp.
∆G≠ a
12.9
syn/anti
ratiob
55/45
GS1
GS2
GS3
(syn)
0.28
TS1
TS2
(anti-out) (antiꢀin)
0.00
0.00
0.00
0.00
0.39
0.22c
0.67
0.95
0.58
1.81
0.00
0.48c
11.55
12.86
13.93
14.42
12.88
23.53
12.44
13.44
14.61
15.93
13.00
25.12
4a
4b
4c
4d
4e
4f
0.47
0.16
1.33
0.001
0.00
14.0
14.9
15.5
14.0
24.5
54/46
55/45
49/51
45/55
51/49
a This value corresponds to the syn/anti interconversion, derived from lineshape simulations. See text
for more details. b determined by NMR integration at appropriate temperature. c The assignment refers
to the relative position of the 2ꢀmethyl groups.
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When the ortho substituents of the aryl rings are both on the same side of the maleimide
scaffold, and a fast interconversion due to πꢀbarrier is taken into account, the conformation has an
average CS symmetry and corresponds to a meso form (syn in Scheme 2). On the contrary, if the ortho
substituents of the arylꢀgroups are arranged on the opposite sides of maleimide (anti configuration), the
resulting C2 symmetry implies a pair of conformational enantiomers. The interconversion pathway
between the syn and anti conformations can be completed through two transition states (TS1 and TS2
in Scheme 2). TS1 represents the crossing of the orthoꢀaryl substituent on the carbonyl group, while
TS2 corresponds to the internal crossing of the orthoꢀsubstituent on the second aryl ring.15a
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In order to experimentally detect these conformations, the hindrance caused by the ortho
substituent on the aryl groups must generate an energy barrier of interconversion (∆G≠) within the
dynamic NMR range (4.5ꢀ22 kcal/mol). When the interconversion barrier is frozen on the NMR
timescale, two conformational diastereoisomers can be observed. However, the assignment of the two
sets of signals to the meso or racemic form cannot be extracted by a simple NMR spectrum, and the use
of a chirality probe is required. To avoid any steric interference with the two aryl groups, a benzyl
group was bonded to the nitrogen of maleimide. The benzyl moiety was chosen for the presence of an
uncoupled CH2 group that acts as the chirality probe, thus displaying different multiplicity depending
on the molecular symmetry.24 The very fast rotation of the benzyl group guarantees that
diastereoisomeric conformations due to different dispositions of the benzyl moiety cannot be observed
in the actual temperature range (i.e. > ꢀ100°C). The effect of the molecular symmetry on the NMR
signal of the CH2 is shown in Figure 1 for compound 4d (Ar = 2ꢀisopropylphenyl). The variable
temperature spectra of other compounds can be found in the Supporting Information (Figures S1ꢀS9).
Due to the slow syn/anti interconversion rate between the two conformations, at room
temperature the signal of the CH2 is very broad and unresolved. At 0 °C the process is slow on the
NMR timescale and the signals of the syn and anti conformers are distinguishable. The singlet in the
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middle of the spectrum (4.826 ppm, cyan) corresponds to the syn conformation (Cs symmetry, 49%),
whereas the AB system (red sections of the spectrum) corresponds to the anti conformation (C2
symmetry, 51%). The lineshape simulation must take into account the coupling constant of the AB spin
system and the exchange of the AB lines with the singlet of the syn form. A second rate constant,
corresponding to the racemization of the anti forms should be also considered.
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Figure 1. Left: temperature dependence of the H benzylic CH2 signal of 4d (600 MHz in C2D2Cl4).
Right: line shape simulation obtained with the rate constants reported.
An accurate simulation was obtained by using only one rate constant which exchanged the AB system
with the single signal of the syn form, without the direct exchange within the AB system. This means
that the racemization of the anti conformer corresponds to a twoꢀstep mechanism with the syn
conformation as an intermediate. The experimental free energy thus corresponds to the transition state
of the antiꢀtoꢀsyn process, and not to the racemization of the conformational enantiomers. To determine
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this energy barrier, a ½ factor must be considered for the rate constants, to account for the possibility of
any of the two rings to generate the syn isomer by rotation. The experimental energy barrier obtained
by lineshape simulation for 4d was 15.5 ± 0.1 kcal/mol, and the ꢀG≠ values were almost invariant with
the temperature, thus implying that the activation entropy was very small or negligible. This situation is
usually found in conformational processes where only an internal rearrangement takes place.7 DFT
calculations had suggested that the lower energy transition state was TS1 (calculated value: 14.4
kcal/mol). This value match satisfactorily the experiment, the difference being only 1.1 kcal/mol (a
summary of the experimental and calculated barriers is reported in Table 1). Although B3LYP does not
consider dispersive forces,25 and despite the use of a relatively small basis set prone to BSSE errors,
this theoretical level confirmed to be able to reproduce with good accuracy the energy barriers of
conformational processes.
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The energy barriers obtained for compounds 4aꢀe suggest that the barrier is controlled only by
steric factors, and the computed energies matched well the relative stability of the two conformational
diastereoisomers, as well as the energy barriers for their interconversion.
B3LYP calculations provided transition energies of 23.5 and 25.1 kcal/mol for the sin/anti
interconversion in the case of compound 4f (Ar = 2ꢀmethylnaphthyl), thus implying the presence of
thermally stable atropisomeric forms. To our delight, the theoretical predictions were validated by
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experimental results. The HꢀNMR spectrum of the crude product showed two sets of signals,
supporting the existence of diastereoisomeric forms, at least on the NMR timescale. Even when the
sample was heated to +120 °C in C2D2Cl4, no evidence of a dynamic exchange was detected, thus
indicating that the barrier was larger than 20ꢀ21 kcal/mol.
When subjected to reverseꢀphase HPLC analysis, the presence of two chromatographic peaks
confirmed the existence of the syn and anti diastereoisomers, although similar retention times thwarted
the physical separation. After some attempts, a celluloseꢀbased enantioselective HPLC column (see
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experimental section for details) was found to be effective in the resolution of the three stereoisomers
(Figure 2). The red and black sections in Figure 2 (top) correspond to the two anti atropisomers, and
the blue section identifies the syn (meso) diastereoisomer. A semiꢀpreparative HPLC approach yielded
solutions that were collected and concentrated in a cold environment (ꢀ10 °C) to freeze out the syn/anti
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interconversion and the anti/anti’ racemization. HꢀNMR spectra recorded in CDCl3 at ꢀ10 °C
confirmed the assignment of the chromatographic peaks. As expected, the meso form (syn) showed a
singlet for the benzylic CH2 signal, while the two anti atropisomers were characterized by the AB
system (see Figure S10 of the Supporting Information).
Figure 2. Top: chromatogram of 4f on enantioselective HPLC column. Bottom: experimental ECD
spectra of the first eluted stereoisomer (red trace) and of the third eluted one (black trace).
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The kinetic of the interconversion process from the syn to anti was performed via HꢀNMR. A
sample of the syn diastereoisomer in CDCl3 was kept at +46 °C and a set of spectra were recorded at
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fixed intervals (180 s), until the equilibrium composition was reached. At the equilibrium, a syn/anti
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ratio of 51/49 was observed. This ratio was confirmed by a second HꢀNMR spectrum of a solution of
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the syn conformer that was kept at +75 °C for 72 hours. The kinetic process was analysed at three
different temperatures (+46 °C, +51 °C and +61 °C). (Figure S11 of the Supporting Information). From
the equilibrium ratio and the slope of the regression lines, a ∆G≠ = 24.5 kcal/mol was derived.26 The
B3LYPꢀcomputed barrier is again very close to the experimental value, the difference being less than
1.0 kcal/mol. This energy barrier corresponds to a halfꢀlife time of about 128 hours at +25 °C.
3ꢀbromoꢀ4ꢀarylmaleimides
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3ꢀBromoꢀ4ꢀaryl substituted compounds (3aꢀ3f) have been also analysed. In these cases only
enantiomeric conformations can be generated by the single stereogenic axis due to the skewed
disposition of the aryl ring. For, the benzylic group is required to detect the enantiomerization process
by NMR. As in the case of compounds 4, two transition states are available (Figure S12 of the
Supporting Information).
Table 2. DFT computed energy barriers of 3ꢀarylꢀ4ꢀbromoꢀNꢀbenzylmaleimides 3aꢀ3f. Also the
experimental energy barriers (∆G≠ in kcal/mol) and the difference with the corresponding 3,4ꢀ
biarylꢀNꢀbenzylmaleimides energy barrier (∆∆G≠ in kcal/mol) are reported.
Entry TS1 (ext) TS2 (int)
∆G≠
14.3
15.3
16.6
17.3
15.7
28.6b
∆∆G≠ a
1.0
11.2
13.6
14.2
15.0
13.2
25.8
12.6
14.6
15.2
15.6
14.8
28.2
3a
3b
3c
3d
3e
3f
1.1
1.3
1.3
1.3
3.6
a This value was obtained by considering the racemization barrier of the corresponding compound 4
b Derived by HPLC analysis, see ref. 28.
They correspond to the crossing of the orthoꢀsubstituent on the carbonyl group or onto the
bromine (TS1 and TS2 in Table 2, respectively). DFT calculations suggested that the preferred pathway
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corresponds to the first hypothesis (i.e. TS1), and that the energy barriers were always higher with
respect to the corresponding bisꢀaryl compounds 4. The experimental energy barriers determined by
dynamic NMR confirmed that all the racemization barriers of compounds 3 were systematically higher
than those of compounds 4 (∆∆G≠ in Table 2).
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These differences can be related to the steric hindrance caused by the spherical bromine in the
transition state, while this effect is negligible in the ground state.27 It is worth noting that the difference
in the experimental free energies of activation (∆∆G≠ in Table 2) between monoꢀ and bisꢀsubstituted
compounds remains similar for each entry, except for compound 3f, where it is 3.6 kcal/mol. This trend
confirms that the transition state for enantiomerization does correspond to TS1, where the different
steric hindrance exerted by the bromine is constant on changing the orthoꢀsubstituent group. Only in
the case of 3f, where both sides of the rotating aryl ring are hindered, the ∆∆G≠ is much higher. In the
latter case, the racemization barrier raised to 28.6 kcal/mol,28 and the two atropisomers were fully
stable also at room temperature. This value is sufficiently high to allow the use of this compound in
asymmetric synthesis, or in the design of atropisomeric catalysts. The separation of the atropisomers
was obtained by means of an amylose enantioselective HPLC column (see the experimental section and
Figure S13 of the Supporting Information).
Absolute configuration
Having in hand the two separated atropisomers of antiꢀ4f and 3f, we pursued the determination
of their absolute configuration. The reference method to assign the absolute configuration (AC) relies
on the Xꢀray anomalous scattering (the “Bijovet method”).29 This approach requires the preparation of
enantiopure single crystals, and the presence of a suitable heavy atom in the molecule (Z > Si when
using MoꢀKα radiation30). In the present case these requirements are not fulfilled, and the assignment
by Xꢀray crystallography is therefore unfeasible. Moreover, during the longꢀlasting crystallization
process, a partial isomerization of antiꢀ4f and racemization of 3f could take place, thus the preparation
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of enantiopure crystals would not be guaranteed. Nevertheless, the determination of the AC of chiral
molecules by chiroꢀoptical techniques like optical rotation (OR), electronic circular dichroism (ECD),
and vibrational circular dichroism (VCD) has recently gained feasibility and reliability thanks to the
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development of the timeꢀdependent density functional theory approach (TDꢀDFT) 31
. In the present case
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the theoretical calculation of ECD spectra was selected for the absolute configuration assignment of
antiꢀ4f. In order to correctly simulate the experimental spectrum, all the available conformations should
be considered, the experimental spectrum being the weighted sum of the populated conformations.31c
The conformational search by MM methods32 suggested that two conformations were available for the
two naphthyl rings (see Figure 3).
Figure 3: Theoretical ECD spectra of the two conformations of M,Mꢀ4f obtained with the TDꢀDFT
method with four different theoretical methods and the 6ꢀ311+G(d,p) basis set. All the spectra were
obtained by applying Gaussian shapes (linewidth = 0.25 eV) to the discrete transitions. The vertical
scale has been reduced by a factor of 20 with respect to the calculated value. On the right are reported
the two optimized structures (relative ZPEꢀcorrected free energies in kcal/mol, distances in Å).
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In one of these the methyl groups point towards the second ring (antiꢀin, as from Scheme 2) and in the
other one they are directed towards the two carbonyl oxygens (antiꢀout in Scheme 2). In addition, two
different dispositions of the benzyl group had to be considered (i.e. that where the phenyl was
perpendicular to the maleimide ring and a second where the phenyl ring had a dihedral of 30° with the
plane of maleimide). After minimization by DFT at the B3LYP/6ꢀ31G(d) level, the antiꢀin and antiꢀout
conformations were found to have very similar energy and only the perpendicular conformation of the
benzyl group was found to be essentially populated (see Figure 3). The electronic excitation energies
and rotational strengths were calculated in the gas phase using TDꢀDFT with four different functionals
to explore whether different types of calculations provide different shapes of the simulated spectra.
Simulations were performed on the previously optimized geometries using the hybrid functionals
BH&HLYP33 and M06ꢀ2X,34 the longꢀrange correlated ωB97XD that includes empirical
dispersion,35,36 and CAMꢀB3LYP that includes long range correction using the Coulomb Attenuating
Method.37 Three explorative tests were performed using different basis sets that proved to be accurate
for these calculations such as the 6ꢀ311++G(2d,p),38 def2ꢀTZVPP39 and 6ꢀ311+G(d,p)38 basis sets with
the CAMꢀB3LYP functional, without appreciable differences (see Figure S14 of the Supporting
Information). For this reason, all the calculations employed the computationally cheaper 6ꢀ311+G(d,p)
basis set. Rotational strengths were calculated in both length and velocity representation, the resulting
values being very similar (RMS differences < 5%). For this reason the errors due to basis set
incompleteness should be very small, or negligible.40
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As shown in Figure 3, the simulated ECD spectra for the two conformations of the M,M
atropisomer are very similar within the same conformation, but the two conformations exhibit nearly
opposite spectra. For this reason the conformationally averaged ECD spectrum will be extremely
sensitive to the population ratio, and a knowledge of the experimental ratio of the two conformers is
necessary to obtain a correct simulation.41 A direct detection of the experimental ratio of the two
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conformations was impossible, being the πꢀbarrier inaccessible to the dynamicꢀNMR technique. Thus
NOE spectra were used to experimentally evaluate this ratio (see Figure 4).42 In both the antiꢀin and
antiꢀout conformers, the 2ꢀmethyl group of each naphthyl ring is spatially close to the hydrogen in
position 3 of the same ring (blue arrows in Figure 3, right), and to the H8 of the second naphthyl ring
(red arrows in Figure 3, right).
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Figure 4. DPFGSEꢀNOE spectra of 4f obtained by saturation of the 2ꢀmethyl groups (600 MHz in
CD3CN, mixing time = 1.5 s). The numbers over the scale represent the normalized integration of the
two NOE peaks. Spectra obtained with different mixing times are reported in S.I.
Depending on the conformation considered,43 the distances from the 2ꢀmethyl to H8 are different, while
the MeꢀH3 distance is the same (2.70 Å). The NOE effect on H3 can thus act as an internal “control”
distance. In the antiꢀin conformation the MeꢀH3/MeꢀH8 distance ratio was calculated as 0.89, whereas
in the antiꢀout conformation the same ratio was 1.03 (Figure 3). The experimental NOE ratio observed
by saturating the 2ꢀmethyl signal (Figure 4) is in between the two limiting values (0.935), thus both the
conformations must be appreciably populated. If the calculated distances are taken into account, the
observed NOE corresponds to a 60:40 (± 15%) ratio of the two conformations (antiꢀin : antiꢀout). This
result is in agreement with the 59:41 ratio based on the computed free energies of the two
conformations (0.00 and 0.21 kcal/mol for the antiꢀin and antiꢀout, respectively).
The experimental ECD spectra of 4f (Figure 2, bottom) shows the characteristic features of the
1ꢀnaphthyl chromophore, in that a weak structured band at 285 nm and intense bands at about 225 nm
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are observed.44 These Cotton effects are certainly due to the La and B transitions,45 polarized along
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the short and long axis of the naphthalene chromophore, respectively. Below 220 nm the absorption
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due to the B transition of the benzyl moiety can also be observed. The structured region between 240
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and 210 nm and in particular the narrow negative band at 231 nm could be the result of two opposite
exciton couplings involving the 1B transition of the two naphthalene rings.46
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Figure 5. Orientations of the B transitions of the two naphthyl rings of 4f for the antiꢀin and antiꢀout
conformations.
In the antiꢀin conformation, the two dipoles of the naphthalene rings form a positive dihedral angle
while in the antiꢀout they form a negative angle (see Figure 5). To confirm this hypothesis and to
exclude any contribution of the benzyl group, we simulated the ECD spectrum of the 3,4ꢀbisꢀ(2ꢀ
methylnaphthyl) maleimide. The simulated spectra are identical to that previously obtained for 4f. In
addition, the analysis of the molecular orbitals involved in the electronic transitions between 230 and
200 nm showed that they are localized mostly on the naphthyl rings (Figures S16 and S17 of the
Supporting Information). When the simulated ECD spectrum of the M,M atropisomer was generated
taking into account the ratio suggested by calculations, (blue, green, red and purple lines in Figure 6)
the matching with the experimental ECD spectrum of the second eluted atropisomer of 4f is quite good,
the best simulation being obtained with the ωB97XD functional.47 To further confirm the reliability of
the assignment, the population ratio of the two conformations was changed by ± 20% without
appreciable worsening of the simulation (see Figure S18 of the Supporting Information). It is therefore
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concluded that the first eluted enantiomer of 4f corresponds to the P,P atropisomer and the second
eluted to the M,M atropisomer.48
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Figure 6. Computed ECD spectra of 4f considering a ratio of 59:41 of the two conformations, and
using different functionals. All the calculations employed the 6ꢀ311+G(d,p) basis set. Black line:
experimental ECD spectrum of the second eluted atropisomer of 4f.
Using the same approach applied to compound 4f, the absolute configuration of 3f was
determined by the simulation of the ECD spectra. Four different conformations were found to be
populated by MM conformational search. Due to presence of a single naphthyl ring, they correspond to
the two dispositions of the naphthyl ring already discussed before, combined with the two available
dispositions of the benzyl ring (Figure S20 of the Supporting Information). The experimental ECD
spectrum shows two opposite Cotton effects that are probably coupled together. At variance with
compound 4f, this single exciton coupling could be due to the stereogenic axis generated by the
naphthyl ring and the maleimide chromophore, or by the naphthyl ring with the benzyl group. The ECD
spectra simulated for the four conformations assuming the M absolute configuration exhibit different
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shapes, in particular in the 230 nm region. To understand whether the 230 nm region of the spectrum
was due the transitions related to maleimide, the MO components of the most intense UV transition
calculated in that region (231 nm) were generated and visualized for the four conformations (Figures
S21ꢀS24 of the Supporting Information). The occupied MO involved were localized mainly on the
maleimide ring whereas the unoccupied orbital corresponded to the LUMO orbital, again localized
exclusively on maleimide. As regards to the second transition calculated at 211 nm, MO analysis
confirmed that it was due to the 1B transition of the naphthalene ring. No significant contribution due to
the benzyl ring was observed for both transitions. For this reason, the observed ECD spectrum can be
discussed in terms of two chromophores disposed in a wellꢀdefined arrangement.
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Figure 7. Top: Calculated ECD spectra for the four possible conformations of 3f. Calculations at the
CAMꢀB3LYP/6ꢀ311+G(d,p) level. Bottom: simulated (red trace) and experimental spectrum (black
trace) of the first eluted atropisomer of 3f.
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Thus the spectrum showed in Figure 7, showing a negative exciton coupling, can be related to
the M atropisomer of 3f.49 This assignment is further supported by the simulation obtained assuming
Boltzmann statistics on the spectra simulated for the four conformation (30:26:24:21 ratio, as from
Boltzmann statistics using ZPE corrected free energies). The experimental ECD spectrum showed that
the intensity ratio between the weak band at 285 nm and the strong band of naphthalene at 221 nm is
very small (as usually happens), whereas the same ratio was much larger in the case of the ECD
spectrum of 4f (see Figure 2 and 5). This feature further confirms that the spectrum of 4f was
dominated by the two opposite exciton couplings due to the antiꢀin and antiꢀout conformations, that
reduced the intensity of the CD spectrum of the naphthalene transitions in the 225 nm region.
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Conclusions
The planar scaffold of maleimide provides separable atropoisomers when hindered aryl rings
occupy to the 3,4 positions, and 3ꢀbromoꢀ4ꢀarylmaleimides generate atropisomers as well. The latter
can be further functionalized and take advantage of the larger racemization barrier. DFT calculations at
the B3LYP/6ꢀ31G(D) level were able to predict the energy barriers for racemization with good
accuracy, and can help in the design of new atropisomeric compounds to be used in asymmetric
synthesis. The absolute configuration of the most hindered compounds was determined by theorethical
simulation of the ECD spectrum by means of TDꢀDFT calculations supported by NMR conformational
analysis.
Experimental Section
Materials: 3,4ꢀdibromoꢀ1Hꢀpyrroleꢀ2,5ꢀdione, benzyl bromide, 1ꢀbromoꢀ2ꢀmethylnaphthalene, nꢀ
butyllithium, and the boronic acids 2aꢀ2e were commercially available. 2ꢀmethylnaphtyl boronic acid50
and 3,4ꢀdibromoꢀ1ꢀbenzylꢀpyrroleꢀ2,5ꢀdione51 were prepared according to known procedures. Diethyl
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ether and THF have been dried before use by distillation on Na/benzophenone. Chromatography
employed the following stationary phases: Silica gel 60 F254 for the TLC and silica gel 60 Å (230ꢀ400
mesh) for preꢀpurification. All the reactions were performed in dried glassware and under dry nitrogen
atmosphere). Glassware was dried at +70 °C for at least 3 hours immediately before use. Phenomenex
Luna® C18 (10 ꢁm, 100 Å, 250×21.2 mm) semiꢀpreparative column was used to purify the compounds
using mixtures of CH3CN and H2O as eluent. Enantioselective HPLC columns were used to separate
the stable atropisomers of 4f and 3f (Phenomenex LUXꢀcellulose® 2 250×10 mm and Daicel
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Chiralpak® ADꢀH 250×21.2 mm, respectively). Detection wavelength was 254 nm.
1
NMR spectra were recorded using a spectrometer operating at a field of 14.4 Tesla (600 MHz for H,
150.8 for 13C). Chemical shifts are given in ppm relative to the internal standards tetramethylsilane (1H
and 13C) or relative to the residual peak of the solvents. The 600 MHz 1H spectra were acquired using a
5 mm dual direct probe with a 9000 Hz spectral width, 2.0 ꢁs (20° tip angle) pulse width, 3 s
acquisition time and 1 s delay time. A shifted sine bell weighting function equal to the acquisition time
(i.e., 3 s) was applied before the Fourier transformation. The 150.8 MHz 13C spectra were acquired
under proton decoupling conditions with a 38000 Hz spectral width, 4.2 ꢁs (60° tip angle) pulse width,
1 s acquisition time and 1 s delay time. A line broadening function of 1–2 Hz was applied before the
Fourier transformation. Assignment of the carbons multiplicity were obtained by means of the DEPT
sequences.
General synthetic procedure: 1ꢀbenzylꢀ3,4ꢀdibromoꢀ1Hꢀpyrroleꢀ2,5ꢀdione 1 (1 mmol) was dissolved
in dry THF (5 mL), then the appropriate boronic acid (2 mmol), cesium carbonate (2.5 mmol) and the
palladium catalyst Pd(PPh3)4 or Pd(OAc)2 were added. The stirred solution was kept at reflux for 2
hours or at +40 °C overnight (Table 3 summarizes the experimental conditions). Et2O and H2O were
then added and the extracted organic layer was dried (Na2SO4), filtered on silica gel and concentrated
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at reduced pressure. The crude products were purified by semiꢀpreparative HPLC on C18 column, to
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obtain analytically pure samples of 3aꢀ3f and 4aꢀ4f.
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Table 3 : Summary of the synthetic details.
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Entry (yield %)
3a (30)
Entry (yield %)
4a (32)
Catalyst Temperature
Time
2 h
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
reflux
+40 °C
reflux
+40 °C
reflux
reflux
3b (37)
4b (18)
overnight
2 h
3c (35)
4c (30)
3d (27)
4d (10)
overnight
2 h
3e (28)
4e (20)
3f (13)
4f (6)
2 h
1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(oꢀtolyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3a). Yield: 0.104 g (30%) as white waxy solid. 1H
NMR (600 MHz, CD2Cl2, 5.33 ppm, +25 °C): δ 2.27 (s, 3H), 4.79 (s, 2H), 7.22 (d, J= 7.7 Hz, 1H),
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7.28ꢀ7.44 (m, 8H). C NMR (150.8 MHz, CD2Cl2, 54.0 ppm, +25 °C): δ 20.6 (CH3), 43.1 (CH2),12.3
(CH), 127.1 (Cq), 128.0 (Cq), 128.5 (CH), 128.9 (2CH), 129.3 (2CH), 129.8 (CH), 130.8 (CH), 131.3
(CH), 136.6 (Cq), 137.7 (Cq), 144.3 (Cq), 165.7 (Cq), 168.6 (Cq). HPLC: CH3CN:H2O 82:18 v:v, tR =
7.78 min HRMS (EI) m/z calcd. for C18H14BrNO2 [M•+]: 355.02079. Found: 355.0210.
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1ꢀbenzylꢀ3,4ꢀdiꢀoꢀtolylꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4a). Yield: 0.118 g (32%) as white amorphous solid. H
NMR (600 MHz, CD2Cl2, 5.33 ppm, +25 °C): δ 2.06 (s, 6H), 4.84 (s, 2H), 7.09 (d, J=7.6 Hz, 2H), 7.17
(t, J=7.6 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.29 (td, J=7.6, 1.1 Hz, 2H), 7.31ꢀ 7.35 (m, 1H), 7.38 (t,
J=7.43 Hz, 2H), 7.44 (d, J=7.1 Hz, 2H). 13C NMR (150.8 MHz, CD2Cl2, 54.0 ppm, +25 °C): δ 20.6 (2
CH3), 42.6 (CH2), 126.2 (2 CH), 128.3 (CH), 128.7 (2 CH), 129.2 (2 CH), 129.4 (2 Cq), 130.1 (2 CH),
130.6 (bs, 2 CH), 131.2 (2 CH), 137.3 (2 Cq), 137.7 (Cq), 141.1 (2 Cq), 170.8 (2 Cq). HPLC:
CH3CN:H2O 82:18 v:v, tR = 10.58 min. HRMS (EI) m/z calcd for C25H21NO2 [M•+]: 367.15723. Found:
367.1572.
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1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(2ꢀethylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3b). Yield: 0.135 g (37%) as white waxy
solid. 1H NMR (600 MHz, C2D2Cl4, 6.00 ppm, +25 °C): δ 1.17 (t, J= 7.5 Hz, 3H), 2.55 (q, J= 7.5 Hz,
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2H), 4.80 (bs, benzylic CH2), 7.18 (d, J= 7.6 Hz, 1H), 7.30ꢀ 7.42 (m, 7H), 7.48 (t, J= 7.6, 1H). C
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NMR (150.8 MHz, C2D2Cl2, 74.0 ppm, +25 °C): δ 15.25 (CH3), 26.9 (CH2), 42.8 (CH2), 126.1 (CH),
126.6 (Cq), 126.9 (CH), 128.3 (CH), 128.6 (CH), 129.0 (2 CH),129.4 (CH), 130.7 (Cq), 135.8 (Cq),
143.1 (Cq), 144.2 (Cq), 165.2 (Cq), 168.4 (Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 9.25 min. HRMS
(EI):calcd for C19H16BrNO2 [M•+]: 369.03644. Found: 369.0360.
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1ꢀbenzylꢀ3,4ꢀbis(2ꢀethylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4b). Yield: 0.070 g (18%) as white amorphous
solid.1H NMR (600 MHz, CD3CN, 1.96 ppm, +60 °C): δ 1.07 (t, J = 7.6 Hz, 6H), 2.49 (q, J= 7.6 Hz,
4H), 4.82 (s, 2H), 7.11 (d, J= 7.7 Hz, 2H), 7.17 (t, J= 7.6 Hz, 2H), 7.30ꢀ7.37 (m, 5H), 7.40 (bd, 4H).
13C NMR (150.8 MHz, CD3CN, 118.3 ppm, +60 °C): δ 15.2 (2CH3), 27.3 (2CH2), 43.1 (CH2), 126.8
(2CH), 128.8 (2CH),128. 8 (CH), 129.6 (2Cq), 129.7 (2CH), 129.9 (2CH), 130.9 (2CH), 131.3 (2CH),
138.4 (Cq), 142.6 (2Cq), 144.5 (2Cq), 171.9 (2Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 15.10 min.
HRMS (EI) m/z calcd for C27H25NO2 [M•+]: 395.18853. Found: 395.1881.
1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(2,3ꢀdimethylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3c) Yield: 0.130 g (35%) as white
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waxy solid. H NMR (600 MHz, C2D2Cl4, 6.00 ppm, +25 °C): δ 2.16 (s, 3H), 2.35 (S, 3H), 4.78 (d,
J=14.59 Hz, 1H), 4.82 (d, J=14.59 Hz, 1H), 7.09 (d, J= 7.6 Hz, 1H), 7.235 (t, J= 7.6 Hz, 1H), 7.28ꢀ7.44
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(m, 6H). C NMR (150.8 MHz, C2D2Cl4, 74.0 ppm, +25 °C): δ 18.0 (CH3), 20.5 (CH3), 42.7 (CH2),
125.8 (CH), 126.3 (Cq), 127.1 (CH), 128.3 (2 CH), 129.0 (2 CH), 132.0 (Cq), 135.6 (Cq), 135.8 (Cq),
138.2 (Cq), 144.2 (Cq), 165.3 (Cq), 168.5 (Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 9.20 min. HRMS
(EI) m/z calcd for C19H16BrNO2 [M•+]: 369.03644. Found: 369.0358.
1ꢀbenzylꢀ3,4ꢀbis(2,3ꢀdimethylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4c). Yield: 0.118 g (30%) as white
amorphous solid.1H NMR (600 MHz, CDCl3, +50 °C): δ 1.96 (s, 6H), 2.22 (s, 6H), 4.83 (s, 2H), 6.88
(bd, 2H), 7.02 (bt, 2H), 7.12 (bd, 2H), 7.21ꢀ7.40 (m, 3H), 7.45 (bd, 2H). 13C NMR (150.8 MHz, CDCl3,
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77.0 ppm, +50 °C): δ 17.4 (2 CH3), 20.2 (2 CH3), 42.2 (CH2), 125.5 (2 CH), 127.8 (3 CH), 128.6 (2
CH), 128.7 (2 CH), 128.9 (2 Cq), 131.0 (2 CH), 135.4 (2 Cq), 136.7 (Cq),137.4 (2 Cq), 141.2 (2 Cq),
170.4 (2 Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 14.51 min. HRMS (EI) m/z calcd for C27H25NO2
[M•+]: 395.18853. Found 395.1880.
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1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(2ꢀisopropylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3d). Yield: 0.104 (27%) g as white
waxy solid. 1H NMR (600 MHz, C2D2Cl4, 6.00 ppm, +25 °C): δ 1.18 (d, J=6.7 Hz, 3H), 1.24 (d, J= 6.7
Hz, 3H), 2.69 (sett, J= 6.7 Hz, 1H), 4.77 (d, J=14.6 Hz, 1H), 4.81 (d, J=14.6 Hz, 1H), 7.13 (d, J= 7.7
Hz, 1H), 7.30 (t, J= 7.5 Hz, 1H), 7.32ꢀ7.42 (m, 5H), 7.43ꢀ7.52 (m, 2H). 13C NMR (150.8 MHz,
C2D2Cl4, 74.0 ppm, +25 °C): δ 23. 9 (CH3), 24.5 (CH3), 31.9 (CH), 42.8 (CH2), 126.0 (Cq), 126.1
(CH), 126.2 (CH), 127.1 (Cq), 128.3 (CH), 128.6 (2CH), 129.0 (2CH), 129.2 (CH), 130.8 (CH), 135.8
(Cq), 144.6 (Cq), 148.0 (Cq), 165.2 (Cq), 168.5 (Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 12.15 min
HRMS (EI) m/z calcd for C20H18BrNO2 [M•+]: 383.05209. Found: 383.0525.
1ꢀbenzylꢀ3,4ꢀbis(2ꢀisopropylphenyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4d). Yield: 0.042 g (10%) as white
amorphous solid. NMR spectra showed the presence of the two conformations syn (49%) and anti
(51%). 1H NMR (600 MHz, CDCl3, 0 °C): δ 0.72 (d, 6H anti, J=6.4 Hz), 0.81 (d, 6 H syn, J= 6.4 Hz),
1.145 (d, 6 H anti, J= 6.4 Hz), 1.22 (d, 6 H syn, J= 6.4 Hz), 2.65 (quint, 2H anti, J= 6.4 Hz), 2.70
(quint, 2 H syn, J= 6.8 Hz), 4.79 (d, 1H anti, J= 14.5 Hz), 4.835 (s, 2 H syn), 4.88 (d, 1 H anti, J=14.5
13
Hz), 6.99 (bt, 4 H), 7.08ꢀ7.16 (m, 4 H), 7.24ꢀ7.40 (m, 14 H), 7.49 (bt, 4 H). C NMR (150.8 MHz,
CDCl3, 77.0 ppm, 0 °C): δ 23.0 (2 CH3), 23.2 (2 CH3), 24.7 (2 CH3), 25.1 (2 CH3), 31.1 (4 CH), 42.15
(CH2), 42.2 (CH2), 125.6 (2CH), 125.7 (2CH), 126.1 (2CH), 126.4 (2CH), 126.6 (2 Cq), 126.7 (2Cq),
127.8 (2 CH), 128.7 (4 CH), 128.8 (2 CH), 128.9 (2CH), 129.8 (2CH), 129.9 (2CH), 129.9 (2CH),
130.4 (2CH), 136.4 (2 Cq), 136.5 (2 Cq), 140.3 (2 Cq), 140.6 (2 Cq), 147.7 (2 Cq), 148.0 (2 Cq), 170.6
(4 Cq). HPLC: CH3CN:H2O 82:18 v:v, tR = 21.34 min. HRMS (EI) m/z calcd for C29H29NO2 [M•+]:
423.21983. Found: 423.2192
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1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(naphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3e) Yield: 0.110 (28%) g as white
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amorphous solid. H NMR (600 MHz, CDCl3, +25 °C): δ 4.85 (s, 2H), 7.29ꢀ7.4 (m, 3H), 7.46 (d, J=
6
7
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7.2 Hz, 2H), 7.48ꢀ7.63 (m, 5H), 7.92 (d, J= 8.3 Hz, 1H), 7.995 (d, J= 8.3 Hz, 1H). C NMR (150.8
8
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MHz, CDCl3, 77.0 ppm, +25 °C): δ 42.8 (CH2), 124.9 (CH), 125.0 (Cq), 125.5 (CH), 126.5 (CH),126.8
(CH), 127.1 (Cq), 128.2 (CH), 128.5 (CH), 128.81 (CH), 128.83 (2CH), 128.9 (2CH), 129.9 (Cq), 131.1
(CH), 133.6 (Cq), 135.8 (Cq), 142.4 (Cq), 165.1 (Cq), 168.4 (Cq). HPLC: CH3CN:H2O 90:10 v:v, tR =
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+
5.94 min. HRMS (ESIꢀOrbitrap) m/z calcd for C21H15BrNO2 [M+H+]: 392.02807. Found: 392.02914.
1ꢀbenzylꢀ3,4ꢀdi(naphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4e). Yield: 0.088 g (20%) as white amorphous
1
solid. H NMR (600 MHz, C2D2Cl4, 6.00 ppm, +60 °C): δ 4.92 (s, 2H), 7.24 (t, J= 7.6 Hz, 2H), 7.32ꢀ
7.38 (m, 7H), 7.40 (t, J=7.6 Hz, 2H), 7.50 (d, J=7.6 Hz, 2H), 7.59 (bd, 2H), 7.74 (d, J= 8.1 Hz, 2H),
13
7.78 (d, J= 7.6 Hz, 2H). C NMR (150.8 MHz, C2D2Cl4, 74.0 ppm, +60 °C): δ 42.5 (CH2), 125.1 (2
CH), 125.2 (2 CH), 126.1 (2 CH), 126.4 (2 CH), 126.6 (2 Cq), 127.9 (CH), 128.4 (2 CH), 128.5 (2
CH), 128.7 (2 CH), 128.8 (2 CH), 130.3 (2 CH), 130.7 (2 Cq), 133.4 (2 Cq), 136.5 (Cq), 140.4 (2 Cq),
170.4 (2 Cq). HPLC: CH3CN:H2O 90:10 v:v, tR = 7.23 min HRMS (ESIꢀOrbitrap): m/z calc for
+
C31H22NO2 [M+H+]: 440.16451. Found: 440.16529.
1ꢀbenzylꢀ3ꢀbromoꢀ4ꢀ(2ꢀmethylnaphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (3f). Yield: 0.053 g (13%) as
1
white amorphous solid. H NMR (600 MHz, CDCl3, +25 °C): δ 2.37 (s, 3H), 4.87 (s, 2H), 7.30ꢀ7.36
(m, 1H), 7.37ꢀ7.40 (m, 2H), 7.41ꢀ7.49 (m, 6H), 7.86ꢀ7.90 (m, 2H). 13C NMR (150.8 MHz, CDCl3, 77.0
ppm, +25 °C): δ 20.6 (CH3), 42.8 (CH2), 123.2 (Cq), 124.3 (CH), 125.6 (CH),127.0 (CH), 128.1 (CH),
128.4 (CH), 128.5 (3CH), 128.8 (2CH), 129.2 (Cq), 130.2 (CH), 130.6 (Cq), 131.8 (Cq), 135.2 (Cq),
135.8 (Cq), 143.6 (Cq), 164.9 (Cq), 168.0 (Cq). ChiralPak ADꢀH (5 ꢁm, 250ꢀ20 mm, 20 mL/min, 254
nm, +25 °C) semiꢀpreparative HPLC column has been used for the separation of the atropisomers and
for the kinetic study; hexane:isoꢀpropanol 90:10 v:v, tR 6.89 and 9.55 min. HRMS (ESIꢀOrbitrap): m/z
+
calc for C22H17BrNO2 [M+H+]: 406.04372. Found: 406.04453.
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1ꢀbenzylꢀ3,4ꢀbis(2ꢀmethylnaphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrroleꢀ2,5ꢀdione (4f). total yield (as syn + anti): 0.028
g (6%) as slightly yellow waxy solid. Syn: 1H NMR (600 MHz, CDCl3, ꢀ10 °C): δ 2.24 (s, 6H), 4.95 (s,
2H), 7.12 (t, J= 7.6 Hz, 2H), 7.20 (d, J= 8.3, 2H), 7.27ꢀ7.29 (m, 2H), 7.34ꢀ7.42 (m, 3H), 7.51 (d, J= 7.0
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Hz, 2H), 7.60 (d, J= 8.6 Hz, 2H), 7.64ꢀ7.70 (m, 4H). C NMR (150.8 MHz, CDCl3, 77.00 ppm, ꢀ10
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°C): δ 21.13 (CH3), 42.29 (CH2), 124.30 (2Cq), 124.80 (2CH), 125.06 (2CH)126.11 (2CH), 127.86
(CH), 128.15 (2CH), 128.45 (2CH), 128.59 (2CH), 128.80 (2CH), 129.71 (2CH), 131.00 (2Cq), 131.58
1
(2Cq), 135.41 (2Cq), 136.44 (Cq), 141.92 (2Cq), 170.13 (2Cq). Anti H NMR (600 MHz, CDCl3, ꢀ10
°C): δ 2.03 (s, 6H), 4.95 (AB system, J= 14.75 Hz, 2H), 7.15 (d, J= 8.44 Hz, 2H), 7.27ꢀ7.42 (m, 7H),
13
7.52 (d, J= 7.73 Hz, 2H), 7.56 (d, J= 7.73 Hz, 2H), 7.69 (d, J= 8.5 Hz, 2H), 7.72ꢀ7.76 (m, 2H). C
NMR (150.8 MHz, CDCl3, 77.0 ppm, ꢀ10 °C): δ 21.5 (CH3), 42.3 (CH2), 124.1 (2Cq), 125.0 (2CH),
125.2 (2CH), 126.2 (2CH),127.9 (CH), 128.3 (2CH), 128.5 (2CH), 128.6 (2CH), 128.8 (2CH), 129.7
(2CH), 131.0 (2Cq), 131.7 (2Cq), 136.0 (2Cq), 136.4 (Cq), 142.2 (2Cq), 170.3 (2Cq). Lux Celluloseꢀ2
HPLC column was used to separate the three stereoisomers. (5 ꢁm, 100 Å, 250ꢀ10.00 mm,
hexane:isopropanol 90:10 v:v, 5 mL/min, detection at 254 nm, +25 °C); tR syn = 15.88 min, tR anti:
+
12.62 and 16.92 min. HRMS (ESIꢀOrbitrap): m/z calc. for C33H26NO2 [M+H+]: 468.19581. Found:
468.19726.
Variable temperature NMR spectra. The low temperature spectra were obtained by using a flow of
dry nitrogen which entered into an inox steel heatꢀexchanger immersed in liquid nitrogen and
connected to the NMR probe head by a vacuumꢀinsulated transfer line. Temperature calibrations were
performed before the experiments, using a digital thermometer and a Cu/Ni thermocouple placed in an
NMR tube filled with isopentane. The conditions were kept as equal as possible with all subsequent
work. The uncertainty in the temperature measurements can be estimated from the calibration curve as
±1 °C. The spectra above ambient temperature were calibrated by the same thermocouple placed in a
NMR sample filled with tetrachloroethane. The uncertainty in the highꢀtemperature range can be
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estimated from the calibration curve as ±1 °C. Line shape simulations were performed using a PC
version of the QCPE DNMR6 program.52 Electronic superimposition of the original and the simulated
spectra enabled the determination of the most reliable rate constants at a few different temperatures.
These constants provided the free energies of activation (ꢂG≠) by means of the Eyring equation.53
Within the experimental uncertainty, the latter values were found essentially invariant in the examined
temperature range, thus implying an almost negligible activation entropy ꢂS≠, as observed in the
majority of conformational processes investigated by dynamic NMR.7 The NOE experiments on antiꢀ
4f were performed in CD3CN at +10°C by means of the DPFGSEꢀNOE sequence.54 To selectively
irradiate the methyl signal, a 50 Hz wide shaped pulse was calculated with a refocusingꢀSNOB shape
and a pulse width of 37 ms. Six spectra using different mixing times (0.25, 0.5, 0.75, 1.0, 1.25 and 1.5
s) were acquired to provide the growing curve of the NOEs. In the observed range the grow was linear,
and the average NOE ratio between the two aromatic peaks showed in figure 4 was 57:43.
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ECD spectra. ECD spectra were recorded at +25 °C in acetonitrile solutions. The concentrations of
the samples were tuned to obtain a maximum absorbance of about 0.8 in the UV spectrum using a 0.2
cm path length. Final concentrations were 2•10ꢀ5 M and 5•10ꢀ5 M for 4f and 3f, respectively. Spectra
were recorded in the 190ꢀ400 nm interval, and 4 scans were summed. Reported ꢀε values are
expressed as L molꢀ1cmꢀ1.
Calculations The conformational searches were preliminarily carried out by means of the Molecular
Mechanics Force Field (MMFF), using the MonteꢀCarlo methods.32 The most stable conformers thus
identified were subsequently by DFT computations, that were performed by the Gaussian 09 rev A.02
series of programsError! Bookmark not defined. using standard optimization parameters. All the calculations
employed the B3LYP hybrid HFꢀDFT method55 and the 6ꢀ31G(d) basis sets. Harmonic vibrational
frequencies were calculated for all the stationary points. As revealed by the frequency analysis,
imaginary frequencies were absent in all ground states whereas one imaginary frequency was
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associated with each transition state. Visual inspection of the corresponding normal mode56 validated
the identification of the transition states. The energy values listed in Tables 1 and 2 derive from total
electronic energies. In general, these give the best fit with experimental DNMR data57 and for this
reason the computed values have not been corrected for zeroꢀpoint energy contributions or other
thermodynamic parameters. This approach avoids artefacts due to the ambiguous choice of the
adequate reference temperature and from the idealization of lowꢀfrequency vibrators as harmonic
oscillators.58
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ECD simulations The ECD spectra of antiꢀ4f and 3f were simulated by means of TDꢀDFT
calculations. The electronic excitation energies and rotational strengths have been calculated in the gas
phase using the geometries obtained at the B3LYP/6ꢀ31G(d) level with the CAMꢀB3LYP,37
BH&HLP,33 M06ꢀ2X34 and ωB97XD35 functionals. All the calculations employed the 6ꢀ311+G(d,p)
basis set. Explorative simulations were performed also with the 6ꢀ311++G(2d,p) and def2/TZVPP
basis sets. Rotational strengths were calculated in both length and velocity representation, the resulting
values being very similar (differences below 5%). For this reason BSSE errors should be very small.40
The simulated spectra were obtained using the first 70 calculated transitions (lowest wavelength about
150 nm) and applying a 0.25 eV line width. The simulated spectra resulting from the Boltzmannꢀ
averaged sum of the conformations were redꢀshifted by 10ꢀ15 nm to get the best simulations with the
experimental spectra.
Acknowledgements
Financial contribution was received from the University of Bologna (RFO funds 2010 and 2011). The
authors thank Professor Lodovico Lunazzi for helpful discussions and proofreading of the manuscript.
Supporting Information
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VT spectra of 3aꢀ3e, 4aꢀ4c, 4e; NMR spectra of the two diastereoisomers of 4f; kinetic data for the
syn/anti interconversion of 4f; stereodynamic pathways of compounds 3; enantioselective HPLC of
compound 3f, simulated ECD spectra of the two conformations of 4f; molecular orbitals of the antiꢀin
and antiꢀout conformation of 4f involved in the three strongest CD transitions; simulations of the
experimental ECD spectrum of the second eluted enantiomer of 4f using different ratios of the two
conformations; NOE spectra of antiꢀ4f with different mixing times, Simulated and experimental VCD
spectrum of 4f; 3D views of the four conformations of compound 3f; molecular orbitals of the GS1,
GS2, GS3 and GS4 conformation of 3f involved in the CD transitions calculated at 231 nm and 211
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nm, Computational details of 3aꢀ3f and 4aꢀ4f; H and 13C NMR spectra of 3aꢀ3f and 4aꢀ4f. This
material is available free of charge via the Internet at http://pubs.acs.org/.
References
† This paper is respectfully dedicated to the memory of our colleague and friend Professor Gian Piero
Spada.
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32) MonteCarlo search with the MMFF force field, as implemented in TITAN 1.0.5, Wavefunction
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Becke88
33) In Gaussian 09 the BH&HLYP functional has the form: 0.5*EXHF + 0.5*EXLSDA + 0.5*ꢂEX
+
LYP
EC
.
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42) Despite the fast interconversion rate, the transientꢀNOE technique gives valuable information about
the ratio of the conformations because the observed enhancement is the result of the weighted sum of
the NOEs of each conformation.
43) Distances were calculated on the optimized structure as from T.D.W. Claridge, HighꢀResolution
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