Atropisomers of hindered triarylisocyanurates: Structure, conformation, stereodynamics, and absolute configuration

Article abstract of DOI:10.1021/jo300192n

The syn and anti diastereoisomers of some 1,3,5-triarylisocyanurate derivatives were isolated and their configuration assigned by NOE experiments and by X-ray diffraction. The kinetics of the syn/anti interconversion were determined, and the experimental

Full text of DOI:10.1021/jo300192n

Article
pubs.acs.org/joc
Atropisomers of Hindered Triarylisocyanurates: Structure,
Conformation, Stereodynamics, and Absolute Configuration
Lodovico Lunazzi, Michele Mancinelli, and Andrea Mazzanti*
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
S
* Supporting Information
ABSTRACT: The syn and anti diastereoisomers of some 1,3,5-
triarylisocyanurate derivatives were isolated and their configuration
assigned by NOE experiments and by X-ray diffraction. The kinetics of
the syn/anti interconversion were determined, and the experimental
activation energies matched satisfactorily the values predicted by DFT
computations. Low-temperature NMR spectra were employed to
determine the rotation barrier of N-bonded unhindered aryl
substituents: these barriers, too, are satisfactorily reproduced by DFT
computations. In the case of racemic diastereoisomers, the two
expected enantiomers (atropisomers) were isolated by enantioselective
HPLC and the absolute configuration established by DFT simulation
of the electronic and vibrational circular dichroism spectra.
a physical separation; they can nonetheless be detected by
NMR spectroscopy, usually at low temperature.7,8,12−15
INTRODUCTION
■
Isocyanurate (1,3,5-triazinane-2,4,6-trione) is obtained from the
cyclotrimerization of isocyanate1 and is used to modify the
physical properties of polyurethane foams and coating
materials.2 Polymeric blends of isocyanurates show increased
thermal resistance, flame retardation, chemical resistance, and
film-forming characteristics.3 For example, triaryl isocyanurates
are often used as activators for the polymerization and
postpolymerization of ε-caprolactam in the production of
nylons with high melt viscosities.4 Triallyl isocyanurate has
been used in the preparation of flame-retardant laminating
materials for electrical devices as well as in the preparation of
copolymer resins that are water-resistant, transparent, and
impact-resistant.5 Recently, the rigid structure of isocyanurate
has found interesting application in the fields of chiral
discrimination and low toxicity drug delivery.6 Isocyanurate is
a suitable framework molecule for designing host molecules to
realize chiral recognition, since the multistereogenic centers on
the N-substituents are organized on an inflexible six-membered
isocyanurate ring and then work cooperatively.6
RESULTS AND DISCUSSION
■
Isocyanurate is a six-membered ring and, although not
aromatic, is nevertheless a rather rigid system. Quite
surprisingly, DFT calculations at the B3LYP/6-31G(d) level
predict that the stereoisomers arising from the restricted
rotation of the aryl groups in 1,3,5-tri-ortho-tolyl-isocyanurate
(i.e., 1,3,5-tri-ortho-tolyl-1,3,5-triazinane-2,4,6-trione) 1 (see
Scheme 1) have an interconversion barrier as high as 25.9
Scheme 1
When a six-membered cyclic planar moiety (e.g., a benzene
ring) bears a number of bulky aromatic substituents without a
local C2 symmetry axis, a number of stereoisomeric forms can
exist. This is because the substituents undergo a restricted
rotation process that creates a number of out-of-plane
structures. When these aryl groups are sufficiently bulky (for
example, bearing an ortho substituent) and they are bonded to
positions 1,2 (i.e., vicinal substituents), the corresponding
stereoisomers are often stable enough to be physically
separable.7−12 On the other hand, if the six-membered scaffold
bears the aryl rings in the meta or para positions, the
interconversion of the stereoisomers is usually too fast to allow
kcal mol−1. This value suggests that it should be possible to
physically separate these forms, despite the fact that the ortho-
tolyl substituents are not in a vicinal position. To verify such a
prediction, compound 1 was prepared by reacting 1-isocyanato-
Received: January 25, 2012
Published: March 2, 2012
© 2012 American Chemical Society
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2-methylbenzene with a catalytic amount of potassium acetate
at +130 °C.
The reaction actually provided two diastereoisomers (in a
73:27 ratio) that could be separated by semipreparative HPLC.
The anti structure with Cs symmetry (Scheme 2) was assigned
negligible energy difference (0.15 kcal mol−1) between 1a
and 1b (Scheme 2).
The barrier measured in the case of 1 confirms the prediction
of the DFT calculations, and its large value implies that, in
derivatives where one of the three ortho-tolyl groups is replaced
by another aromatic substituent having a local 2-fold N−Ar
symmetry axis (C2), the syn and anti diastereoisomers would
correspond, respectively, to a meso (Cs) and to a racemic form
(C2): the latter should be, therefore, separable into a pair of
stable conformational enantiomers (atropisomers).
Scheme 2. DFT Computed Structures of the
Diastereoisomers of 1 and 2 with the Relative Energies (E)
in kcal mol−1
To verify this point, derivative 2, bearing in position 1 the
3,5-bis(trifluoromethyl)phenyl group, was prepared and the
two diastereoisomers were obtained in a 47:53 proportion (2a
and 2b, respectively). They could be separated by semi-
preparative HPLC, and the corresponding theoretical struc-
tures, as obtained by DFT calculations, are displayed in Scheme
2. The pure major diastereoisomer 2b was kept at +80 °C, and
its interconversion into the minor isomer 2a was followed by
NMR as a function of time. The ratio obtained at the
equilibrium (52:48) was nearly equal to that obtained from the
synthetic process (53:47), suggesting a reaction under
thermodynamic control. The kinetics of this process (Figure
S2 of the Supporting Information) yielded a value for the
interconversion barrier of 26.5 kcal mol−1, to be compared with
the DFT theoretical barrier of 25.4 kcal mol−1 (Table 1).
The NMR spectra of 2a and 2b, unlike the cases of 1a and
1b, do not allow unambiguous assignment of the syn or anti
configuration. Therefore, we resorted to a previously reported
NOE experiment to achieve this assignment.16 In a CD3CN
solution containing the reaction mixture of 2a and 2b, the pairs
of 13C satellites17 of both methyl lines were simultaneously
irradiated. As shown in Figure 1, the lower-field methyl line
(2.337 ppm) of the second eluted (slightly major) compound
2b yields an NOE effect, indicating that this line belongs to the
syn (meso) diastereoisomer, where the hydrogens of the two
methyl groups are sufficiently close to experience a reciprocal
intensity enhancement.18
to the major diastereoisomer (1a) because its NMR spectrum
displayed two methyl signals with a 2:1 intensity ratio.
On the other hand, the minor diastereoisomer showed a
single NMR methyl signal and was, therefore, identified as
having the syn structure 1b (C3v symmetry).
When the isolated minor diastereoisomer syn (1b) was kept
at +70 °C in acetonitrile, the major anti diastereoisomer (1a)
was generated and its population increased, until a 71:29
anti:syn ratio was reached at the equilibrium. This ratio is
essentially the same as that obtained in the synthesis of 1, thus
indicating that the reaction is under thermodynamic control.
The kinetics of the interconversion process (see Figure S1 of
the Supporting Information) was followed by monitoring the
HPLC trace as a function of time and provided a barrier for the
1b (C3v) to 1a (Cs) interconversion equal to 26.6 kcal mol−1
(the barrier from the major 1a to the minor 1b is 27.2 kcal
mol−1, as in Table 1).
On the contrary, irradiation of the 13C satellites does not
produce a NOE effect on the higher-field methyl line (2.331
ppm): the corresponding (slightly minor) diastereoisomer 2a
has, consequently, the anti (racemic) configuration, where the
hydrogens of the two methyl groups are too far apart18 to yield
such an enhancement.
Table 1. Free Energies of Activation (ΔG⧧) for the Dynamic
Processes Measured in 1−4 and, in Parentheses, the DFT
Computed ΔE⧧ Values, Both in kcal mol−1
aryl−N rotation
An independent check of this assignment was obtained by
monitoring the effects on the spectral lines of the third aryl ring
when the temperature is lowered. At ambient temperature, the
rotation of the 3,5-bis(trifluoromethyl)phenyl ring is fast; thus
the different symmetries of the two diastereoisomers 2a and 2b
cannot be distinguished by NMR. However, when the spectrum
is recorded at a temperature sufficiently low as to freeze this
rotation, two possible situations might, in principle, be
encountered:
a
b
compd
syn/anti interconversion
homomerization
c
1
2
3
4
26.6 27.2 (25.9)
26.4 26.5 (25.4)
10.8 (9.7)
12.2 (10.8)
12.3 (10.5)
26.65 26.8 (26.0)
c
a
The first column refers to the measured barrier from the less to the
more stable and the second from the more to the less stable form. The
values in parentheses (third column) refer to the computed barrier
b
from the more to the less stable form. Barriers for rotation of the aryl
(i) If the ground-state conformation of the 3,5-bis-
(trifluoromethyl)phenyl ring is coplanar with that of
isocyanurate, the low-temperature spectrum will not
change so that a single signal19 for the two ortho
hydrogens of the 3,5-bis(trifluoromethyl)phenyl sub-
stituent would still be observed in each diastereoisomer,
since, in both cases, they remain isochronous (they are
homotopic in the anti and enantiotopic in the syn form).
If such a situation occurs, this experiment would not
allow a structural assignment.
c
rings without ortho substituent. Not measurable (see text).
It should be also pointed out that the structure of the major
anti (1a) diastereoisomer is 3-fold degenerate in contrast to 1b;
thus its larger proportion is mainly due to a statistic entropy
factor (RT ln 3). If this correction is considered, the
thermodynamic stabilities of the two forms are quite similar,
a result that agrees with DFT calculations predicting a
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Figure 2. Left: temperature dependence of the signal of the 2,6
hydrogens of the 3,5-bis(trifluoromethyl)phenyl substituent of the
second eluted diastereoisomer 2b in CD2Cl2 at 600 MHz. Right:
simulation obtained with the rate constants reported.
the equilibrium (2b:2a = 52:48) since the two isomers can be
considered, within the experimental uncertainty, to be almost
equally populated.
Figure 1. Bottom: methyl lines (600 MHz in CD3CN) of the 53:47
mixture of 2b and 2a with the 50-fold enhanced 13C satellites in the
inset (the small signals at 2.41 and 2.28 ppm are impurities of the
solvent). Top: spectrum resulting from the simultaneous irradiation of
the 13C satellites, yielding the NOE effect solely for the downfield line
of diastereoisomer 2b (syn, meso).
On the basis of this assignment, the isolated racemic
diastereoisomer anti 2a is expected to show two HPLC peaks
when using an enantioselective chromatographic column, in
that two enantiomers (atropisomers) can be separated.
This was actually verified, as shown in Figure S3 of the
Supporting Information, where a cellulose-based enantioselec-
tive column was employed. The two atropisomers were isolated
by semipreparative HPLC, and the second eluted yielded the
electronic circular dichroism (ECD) spectrum displayed in
Figure 3 (top). This spectrum was theoretically reproduced by
assuming the configuration M,M. For this purpose, use was
made of TD-DFT calculations, because this approach has been
successfully employed several times to assign the absolute
configuration of complex organic molecules.20 In the present
case, the simulation of the ECD spectrum is relatively
straightforward in that only one conformation has to be
taken into account owing to the rigidity of the system. Also, the
vibrational circular dichroism (VCD)21 spectrum of the same
atropisomer was obtained in the region of the carbonyl
absorption, and again, the experimental trace was satisfactorily
simulated by assuming the same M,M configuration (Figure 3,
bottom), thus making even more reliable the assignment of the
M,M absolute configuration to the second eluted atropisomer
of 2a. Both the ECD and the VCD traces of the first eluted 2a
atropisomer displayed opposite phased spectra with respect to
those of Figure 3, thus assigning the P,P configuration to this
atropisomer.
(ii) If, on the contrary, the adopted conformation has the
3,5-bis(trifluoromethyl)phenyl ring orthogonal to that of
isocyanurate, as predicted by calculations, the frozen
rotation would make the mentioned ortho hydrogens
diastereotopic in the syn (meso), but enantiotopic, thus
isochronous, in the anti (racemic) diastereoisomer.
1
The first eluted diastereoisomer 2a displays a single H line
for the ortho hydrogens of the 3,5-bis(trifluoromethyl)phenyl
ring19 at any temperature (down to −100 °C), as expected for
the anti (racemic) configuration. On the contrary, the
corresponding line19 of the second eluted diastereoisomer 2b
broadens on cooling, decoalesces, and eventually splits, at −87
°C, into a pair of equally intense signals separated by 26 Hz (at
600 MHz), as shown in Figure 2. By line-shape simulation, the
rate constants were determined and a rotation barrier of 10.8
kcal mol−1 was obtained (the DFT calculated barrier is 9.7 kcal
mol−1, as in Table 1). This confirms that the second eluted
diastereoisomer 2b has the syn (meso) configuration and also
that the 3,5-bis(trifluoromethyl)phenyl ring is not coplanar
with the isocyanurate plane. The calculations predict indeed
that the 3,5-bis(trifluoromethyl)phenyl substituent is twisted
with respect to the isocyanurate moiety in both 2a anti
(racemic) and 2b syn (meso) and that the anti diastereoisomer
2a appears to be slightly more stable (by 0.08 kcal mol−1) than
the syn 2b (Scheme 2).
To check whether the behavior observed in 2 might be
somewhat affected by the electronic properties of the Ar1
substituent, compound 3 (where Ar1 is a para-methoxyphenyl
group as in Scheme 1) was investigated. As in the case of 2, two
stable diastereoisomers were obtained, the ratio being 40:60.
In view of the approximations of these calculations, such a
small difference does not contradict the experimental ratio at
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enantioselective HPLC, and the first eluted atropisomer yielded
the ECD spectrum and the VCD spectrum (in the region of the
carbonyl absorption)21 displayed in Figure S6 of the Supporting
Information. By making use of the aforementioned TD-DFT
and DFT approaches, respectively, these spectra were
theoretically reproduced by assuming the absolute config-
uration P,P.
In the course of the purification of 3, another derivative,
bearing two para-methoxyphenyl substituents (compound 4 of
Scheme 1), was also isolated (see the Experimental Section).
Contrary to the cases of compounds 1−3, compound 4 cannot
yield configurationally stable diastereomeric forms, owing to
the low rotation barrier of the para-methoxyphenyl groups, and
it exists, consequently, as a single isomer. The barrier to
rotation of the para-methoxyphenyl moiety was again
determined by low-temperature NMR (Figure S7 of the
Supporting Information), and essentially the same value as that
of 3 was obtained (Table 1).
Compound 4 yielded single crystals suitable for X-ray
diffraction so that an experimental structure could be obtained.
As reported in the case of an analogous triphenyl
isocyanurate,22 the planes of the three aryl rings are indeed
almost orthogonal with respect to that of the isocyanurate ring,
as predicted by computations (Figure 4). This provides further
support to the reliability of the DFT calculations used in the
present investigation.
Figure 3. Top: experimental ECD spectrum (in CH3CN) of the
second eluted atropisomer of 2a (green trace) and TD-DFT
simulation (red trace, CAM-B3LYP/6-311++G(2d,p), shifted by +7
nm) assuming the absolute M,M configuration. Bottom: experimental
VCD spectrum (in CCl4) of the carbonyl region of the same
atropisomer (green trace) and DFT simulation (red trace, B3LYP/6-
31+G(2d,p), shifted by −45 nm) assuming the same M,M
configuration.
The low-temperature 13C spectrum of such a mixture showed
that the major signal of the carbons meta to the para-methoxy
group splits into two at −67 °C, whereas the corresponding
minor signal does not. As discussed above for the case of 2, this
proves that the major diastereoisomer (labeled 3b) corresponds
to the syn (meso) and the minor (3a) to the anti (racemic)
structure. The line-shape simulation (Figure S4 of the
Supporting Information) afforded a ΔG⧧ value of 12.2 kcal
mol−1 for the N−Ar1 rotation barrier (DFT computation had
predicted 10.8 kcal mol−1 for this process, as in Table 1). The
barrier measured in 3b is 1.4 kcal mol−1 higher than the
corresponding barrier measured in 2b. As a possible
explanation, the electron-withdrawing properties of the CF3
group substituent in 3 might favor the conjugation of the lone
pair of the nitrogen with the aryl ring in the planar transition
state of 2b, lowering the energy of the transition state and thus
reducing the corresponding rotational barrier. The experimen-
tal difference is rather small, but it is worth to outline that it is
matched by the DFT calculations (predicted energy difference:
1.1 kcal mol−1; experimental difference: 1.4 kcal mol−1).
Figure 4. Experimental X-ray diffraction (left) and DFT computed
structure (right) of compound 4.
On the other hand, three diastereoisomers are expected to
occur when one of the three CO groups of 1 is substituted
by a CS moiety to yield compound 5. The corresponding
structures are indicated as syn (meso) 5a, anti (meso) 5b, and
anti (racemic) 5c (Scheme 3).
Scheme 3. Schematic Representation of the Stereoisomers of
a
5
The major diastereoisomer 3b (syn) was isolated and kept at
+70 °C until the equilibrium with the minor 3a (anti) was
reached. At this temperature, the anti:syn ratio 3a:3b (45:55) is
quite close to that obtained in the synthetic procedure. The
kinetic process was followed by monitoring the methyl NMR
signals as a function of time, and the barrier for the
interconversion of the major into the minor diastereoisomer
was determined to be 26.8 kcal mol−1 (Figure S5 of the
Supporting Information). This value compares well with the
DFT computed value of 26.0 kcal mol−1 (Table 1). The two
atropisomers of 3a were separated by semipreparative
a
The full and hollow dots indicate the position of the methyls above or
under the plane of isocyanurate.
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The synthetic procedure (see the Experimental Section)
actually afforded three diastereoisomers that were separated by
HPLC, the ratio being 39:18:43. The structure 5c was assigned
to the major diastereoisomer (43%) since it displays three
NMR methyl signals with the same intensity, whereas both the
other two (5a and 5b) display two NMR methyl signals, each
with a 2:1 intensity ratio.
To assign the latter structures, we resorted to NOE
experiments. In the case of the minor diastereoisomer (18%),
irradiation of the more intense of the two methyl signals did
not yield any enhancement of the other methyl signal (and vice
versa). Therefore, the minor isomer must have the anti (meso)
structure 5b where the two isochronous (enantiotopic) methyl
groups are remote from the third one. On the contrary, the
same experiment resulted in a large enhancement in the case of
the 39% diastereoisomer (Figure S8 of the Supporting
Information), indicating that its structure is syn (meso) 5a,
because the two isochronous (enantiotopic) methyl groups are
located on the same face as the third methyl and are thus quite
close.
When a solution of each isolated diastereoisomer was kept at
high temperature (+110 °C in C2D2Cl4) for a sufficiently long
time, both the other two diastereoisomers were generated and
the ratio measured at the equilibrium (5a:5b:5c = 39:19:42)
turned out to be the same as that obtained by the reaction.
When the separation was carried out using an enantioselective
HPLC column, four peaks were observed because the peak
corresponding to the racemic diastereoisomer 5c (42%) splits
into two since two atropisomers are present (∼21% each,
Figure S9 of the Supporting Information).
CONCLUSIONS
■
It has been shown that isocyanurates can generate pairs of
atropisomes owing to the hindered rotation about the N−aryl
bond, even in the presence of small ortho substituents in the
aryl ring, such as the methyl group. The availability to prepare
isocyanurates containing two or three different aryl rings could
be interesting for the preparation of a wide class of chiral
diastereoisomers.
EXPERIMENTAL SECTION
■
Materials. The synthesis of isocyanurates 1−4 was carried out
according to a procedure previously reported.24
1,3,5-Tri-o-tolyl-1,3,5-triazinane-2,4,6-trione (1). 1-Isocyanato-2-
methylbenzene (0.13 g, 0.12 mL, 1 mmol) was heated at +130 °C in
the presence of a catalytic quantity of potassium acetate until a white
solid was obtained. After cooling at ambient temperature, the organic
layer was diluted with CH2Cl2 and filtered on silica to remove the
catalyst. The solvent was evaporated and the crude purified by
semipreparative HPLC on a Kromasil-C18 (250 × 10 mm, 5 μm,
CH3CN/H2O 7:3 v/v, 5 mL/min) to obtain the (anti) 1a (0.089 g)
and (syn) 1b (0.033 g) as amorphous solids. Compound 1:
HRMS(EI) m/z calcd for C24H21N3O3: 399.1583. Found: 399.1587.
1a (anti): 1H NMR (600 MHz, CD3CN, 1.94 ppm, +25 °C): δ 2.30
(6H, s), 2.32 (3H, s), 7.31−7.37 (3H, m), 7.37−7.40 (6H, m), 7.40−
7.44 (3H, m). 13C NMR (CD3CN, 118.2 ppm, +25 °C): δ 17.1 (2
CH3), 17.3 (CH3), 127.6 (1 CH), 127.7 (2 CH), 129.4 (2 CH), 129.5
(1 CH), 130.2 (3 CH), 131.57 (2 CH), 131.61 (1 CH), 134.0 (1 Cq),
134.1 (2 Cq), 137.1 (2 Cq-N), 137.4 (1 Cq-N), 148.9 (1 CO),
149.1 (2 CO).
1b (syn): 1H NMR (600 MHz, CD3CN, 1.94 ppm, +25 °C): δ 2.285
(9H, s), 7.34−7.42 (12H, m). 13C NMR (150.8 MHz, CD3CN, 118.2
ppm, +25 °C): δ 17.4 (3 CH3), 128.2 (3 CH), 129.7 (3 CH), 130.6 (3
CH), 131.9 (3 CH), 134.6 (3 Cq), 137.2 (3 Cq-N), 149.3 (3 CO).
1-(3,5-Bis(trifluoromethyl)phenyl)-3,5-di-o-tolyl-1,3,5-triazinane-
2,4,6-trione (2). A mixture of 1-isocyanato-2-methylbenzene (0.13 g,
0.12 mL, 1 mmol) and 1-isocyanato-3,5-bis(trifluoromethyl)benzene
(0.25 g, 0.17 mL, 1 mmol) was heated at +130 °C in the presence of a
catalytic quantity of potassium acetate until a white solid was obtained.
After cooling at room temperature, the organic layer was diluted with
CH2Cl2 and filtered on silica to remove the catalyst. The solvent was
evaporated and the crude purified by preparative HPLC on a Synergy
Polar-RP (250 × 20 mm, 4 μm, CH3CN/H2O 8:2 v/v, 20 mL/min) to
obtain 0.020 g of (2). HRMS(EI) m/z calcd for C25H17N3O3F6:
521.1174. Found: 521.1185.
It has been reported23 that, in the thiocarbonyl compounds,
the UV and ECD bands are noticeably shifted to the red, and
this feature makes the simulations more reliable because the
absorption bands are far away from those of the solvent
(acetonitrile).
The first eluted of the two atropisomers of 5c provided the
ECD spectrum displayed in Figure 5, which was very well
reproduced, using the TD-DFT approach and assuming the
M,M absolute configuration. In the present case, the ECD
spectrum is more intense with respect to that of the
corresponding carbonyl derivatives; thus the simulation is
even more reliable.
The pure meso 2b (53%) and both the enantiomers of 2a (47%)
were isolated by enantioselective HPLC chromatography on a
Chiralcel AD-H column (250 × 20 mm, 5 μm, hexane/iPrOH 98:2
v/v, 20 mL/min).
1
2b (meso): amorphous solid. H NMR (600 MHz, CD3CN, 1.94
ppm, +25 °C): δ 2.34 (6H, s), 7.34−7.43 (8H, m), 8.15 (3H, s). 13C
NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C): δ 17.5 (2 CH3),
123.9 (2 CF3, q, 1JCF = 271.4 Hz), 124.3 (CHpara, sept, 3JCF = 3.86 Hz),
128.1 (2 CH), 129.7 (2 CH), 130.6 (2 CH), 131.0 (2 CHorto, q, 3JCF
=
2
3.06 Hz), 132.0 (2 CH), 132.96 (2 Cq, q, JCF = 34.2 Hz), 134.3 (2
Cq), 137.2 (1 N-Cq), 137.6 (2 N-Cq), 148.9 (1 CO), 149.4 (2 C
O). 19F NMR (564.2 MHz, CD3CN, CFCl3, +25 °C): δ −63.81 (6F).
2a (racemic): amorphous solid. 1H NMR (600 MHz, CD3CN, 1.94
ppm, +25 °C): δ 2.33 (6H, s), 7.33−7.44 (8H, m), 8.15 (3H, s). 13C
NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C): δ 17.6 (2 CH3),
123.9 (2 CF3, q, 1JCF = 271.8 Hz), 124.2 (CHpara, sept, 3JCF = 3.96 Hz),
128.0 (2 CH), 129.7 (2 CH), 130.6 (2 CH), 131.0 (2 CHorto, q, 3JCF
=
2
3.64 Hz), 131.9 (2 CH), 132.95 (2 Cq, q, JCF = 34.2 Hz), 134.4 (2
Cq), 137.2 (1 N-Cq), 137.8 (2 N-Cq), 149.0 (1 CO), 149.4 (2 C
O). 19F NMR (564.2 MHz, CD3CN, CFCl3, +25 °C): δ −63.83 (6F).
1-(4-Methoxyphenyl)-3,5-di-o-tolyl-1,3,5-triazinane-2,4,6-trione
(3) and 1,3-Bis(4-methoxyphenyl)-5-o-tolyl-1,3,5-triazinane-2,4,6-
trione (4). A mixture of 1-isocyanato-2-methylbenzene (0.13 g, 0.12
mL, 1 mmol) and 1-isocyanato-4-methoxybenzene (0.15 g, 0.13 mL, 1
Figure 5. Experimental ECD spectrum (in CH3CN) of the first eluted
atropisomer of 5c (blue trace) and TD-DFT computed simulation
(green trace) obtained assuming the absolute M,M configuration.
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mmol) was heated at +130 °C in the presence of a catalytic amount of
potassium acetate until a white solid was obtained. After cooling at
room temperature, the organic layer was diluted with CH2Cl2 and
filtered on silica to remove the catalyst. The solvent was evaporated
and the crude purified by semipreparative HPLC on a Kromasil-C18
(250 × 10 mm, 5 μm, CH3CN/H2O 7:3 v/v, 5 mL/min) to obtain
0.060 g of (4) and 0.035 g of (3). The latter has HRMS(ESI-Orbitrap)
129.6 (2 CH), 130.2 (1 CH), 130.25 (1 CH), 130.6 (1 CH), 131.9 (1
CH), 131.95 (2 CH), 134.3 (1 Cq), 136.9 (1 Cq), 137.2 (1 Cq), 137.3
(1 N-Cq), 138.97 (1 N-Cq), 139.0 (1 N-Cq), 147.8 (1 CO), 147.9
(1 CO), 178.8 (1 CS).
NMR Spectra. NMR spectra were recorded using a spectrometer
1
operating at a field of 14.4 T (600 MHz for H, 150.8 MHz for 13C).
Chemical shifts are given in parts per million relative to the internal
+
m/z calcd for C24H22N3O4 [M + H]+: 416.1605. Found: 416.1607.
standards tetramethylsilane (1H and 13C) and trichlorofluoromethane
1
The pure meso 3b (60%) and both the enantiomers of 3a (40%)
were separated by enantioselective HPLC chromatography on a
chiralcel AD-H column (hexane/iPrOH 98:2 v/v, 20 mL/min).
(19F). The 600 MHz H spectra were acquired using a 5 mm dual
direct probe with a 9000 Hz spectral width, 2.0 μs (20° tip angle)
pulse width, 3 s acquisition time, and 1 s delay time. A shifted sine bell
weighting function26 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 38 000 Hz
spectral width, 4.2 μs (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. Assignments were obtained by
means of the DEPT sequence. The 564.2 MHz 19F spectra were
acquired with a 100 kHz spectral width, 3 μs (30 tip angle) pulse
width, 0.75 s acquisition time, and 1 s delay time.
The low-temperature spectra were obtained by using a flow of dry
nitrogen that entered into an inox steel heat-exchanger immersed in
liquid nitrogen and connected to the NMR probe head by a vacuum-
insulated 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 2 °C.
Line-shape simulations were performed using a PC version of the
QCPE DNMR6 program.27 Electronic superimposition of the original
and of 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 (ΔG⧧) by means of the Eyring
equation.28 Within the experimental uncertainty, the latter values were
found essentially invariant in the examined temperature range, thus
implying an almost negligible activation entropy ΔS⧧, as observed in
the majority of conformational processes investigated by dynamic
NMR.16b,29 The NOE experiments on 2 were performed as previously
described,16 those on 5 were obtained by means of the standard
DPFGSE-NOE sequence.30 To selectively irradiate the desired signal,
a 50 Hz wide-shaped pulse was calculated with a refocusing-SNOB
shape31 and a pulse width of 37 ms. The mixing time was set to 1.5 s.
ECD and VCD spectra. Standard UV absorption spectra were
recorded at +25 °C in acetonitrile on the racemic mixtures, in the
200−400 nm spectral region. ECD spectra were recorded at +24 °C in
acetonitrile solutions, using a path length of 0.2 cm. Spectra were
recorded in the range of 190−400 nm.
VCD spectra were recorded on a single-PEM Fourier transform
spectrometer using a 4 cm−1 resolution. Spectra were recorded in
CDCl3 solutions in a BaF2 cell (100 μm path length). The
concentrations of the samples were calibrated to obtain an absorbance
in the 0.5−0.7 range for the carbonyl signals; 10 000 scans were
collected (3.5 h). The spectra were calibrated using the internal
calibration files, based on the spectrum of neat (-)-α-pinene. Baseline
artifacts were corrected by subtracting the VCD spectrum of the
second eluted enantiomer to the spectrum of the first one. The final
spectrum was then divided by 2 to obtain the correct ΔA intensity.
Calculations. A conformational search was preliminarily carried
out by means of the molecular mechanics force field (MMFF), using
the Monte Carlo method implemented in the package TITAN 1.0.5.32
The most stable conformers thus identified were subsequently energy-
minimized by DFT computations, which were performed by the
Gaussian 09, rev. A.02, series of programs33 using standard
optimization parameters. All the calculations employed the B3LYP
hybrid HF-DFT method34 and the 6-31G(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 associated
with each transition state. Visual inspection of the corresponding
1
3b (meso): amorphous solid. H NMR (600 MHz, CD3CN, 1.94
ppm, +25 °C): δ 2.30 (6H, s), 3.84 (3H, s), 7.05−7.08 (2H, m), 7.33−
7.44 (10H, m). 13C NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C):
δ 17.45 (2 CH3), 56.1 (1 CH3), 115.3 (2 CH), 127.95 (2 CH), 128.1
(1 N-Cq), 129.74 (2 CH), 130.4 (2 CH), 130.7 (2 CH), 131.8 (2
CH), 134.8 (2 Cq), 137.5 (2 N-Cq), 149.3 (1 CO), 150.0 (2 C
O), 160.85 (1 MeO-Cq).
3a (racemic): amorphous solid. 1H NMR (600 MHz, CD3CN, 1.94
ppm, +25 °C): δ 2.31 (6H, s), 3.84 (3H, s), 7.04−7.08 (2H, m), 7.31−
7.43 (10H, m). 13C NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C):
δ 17.6 (2 CH3), 56.1 (1 CH3), 115.3 (2 CH), 127.9 (2 CH), 128.2 (1
N-Cq), 129.8 (2 CH), 130.3 (2 CH), 130.7 (2 CH), 131.8 (2 CH),
134.9 (2 Cq), 137.8 (2 N-Cq), 149.3 (1 CO), 150.0 (2 CO),
160.8 (1 MeO-Cq).
1,3-Bis(4-methoxyphenyl)-5-o-tolyl-1,3,5-triazinane-2,4,6-trione
(4). Crystalline solid. HRMS(ESI-Orbitrap) m/z calcd for
+
C24H22N3O5 [M + H]+: 432.1554. Found: 432.1543. 1H NMR
(600 MHz, CD2Cl2, 5.33 ppm, +25 °C): δ 2.315 (3H, s), 3.865 (6H, s),
7.04−7.07 (4H, m), 7.32−7.42 (8H, m). 13C NMR (150.8 MHz,
CD2Cl2, 53.67 ppm, +25 °C): δ 17.4 (1 CH3), 55.76 (2 CH3), 114.8 (4
CH), 126.6 (1 CH), 127.35 (2 N-Cq), 128.85 (1 CH), 129.7 (4 CH),
129.9 (1 CH), 131.4 (1 CH), 133.5 (1 Cq), 136.5 (1 N-Cq), 148.7 (2
C O), 149.5 (1 CO), 160.3 (2 MeO-Cq). Single crystals suitable for
X-ray diffraction were obtained by slow evaporation of a THF/CH2Cl2
solution (1:1 v/v).
6-Thioxo-1,3,5-tri-o-tolyl-1,3,5-triazinane-2,4-dione (5). Follow-
ing a reported method,25 1,3,5-trio-tolyl-1,3,5-triazinane-2,4,6-trione
(1) (1 mmol = 400 mg) was reacted with 1.67 mmol of
hexamethyldisiloxane and 0.183 mmol of P4S10 in 1 mL of CH2Cl2
and heated to reflux overnight. After cooling at room temperature, the
organic layer was eluted with CH2Cl2 and filtered on silica to remove
the inorganic layer. The solvent was evaporated, and the crude
(60.4%) was purified by semipreparative HPLC on a Luna-C18(2)
column (250 × 20 mm, 5 μm, CH3CN/H2O 8:2, 20 mL/min).
HRMS(ESI-Orbitrap) m/z calcd for C24H22N3O2S+ [M + H]+:
416.1427. Found: 416.1419. Separation of the four steroisomers (the
two meso forms 5a and 5b and the two enantiomers of 5c) was
achieved by enantioselective HPLC chromatography on a Lux
Cellulose-2 column (250 × 10 mm, 5 μm, hexane/iPrOH 90:10 v/
v, 4 mL/min), as in Figure S9 of the Supporting Information
5a (syn, meso) (39%): amorphous solid. 1H NMR (600 MHz,
CD3CN, 1.94 ppm, +25 °C): δ 2.26 (6H, s), 2.28 (3H, s), 7.35−7.42
(12H, m). 13C NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C): δ
17.3 (2 CH3), 17.4 (1 CH3), 128.25 (1 CH), 128.3 (2 CH), 129.4 (2
CH), 129.5 (1 CH), 130.3 (2 CH), 130.7 (1 CH), 131.9 (2 CH),
131.9 (1 CH), 134.3 (1 Cq), 136.6 (2 Cq), 136.9 (1 Cq-N), 138.9 (2
N-Cq), 147.9 (2 CO), 178.8 (1 CS).
1
5b (anti, meso) (18.0%): amorphous solid. H NMR (600 MHz,
CD3CN, 1.94 ppm, +25 °C): δ 2.30 (6H, s), 2.335 (3H, s), 7.36−7.41
(12H, m). 13C NMR (150.8 MHz, CD3CN, 118.2 ppm, +25 °C): δ
17.4 (2 CH3), 17.7 (1 CH3), 127.97 (1 CH), 128.0 (2 CH), 129.5 (2
CH), 129.7 (1 CH), 130.2 (2 CH), 130.7 (1 CH), 131.9 (2 CH),
132.0 (1 CH), 134.25 (1 Cq), 137.0 (2 Cq), 137.7 (1 Cq-N), 139.0 (2
NN-C), 147.9 (2 CO), 178.8 (1 CS).
1
5c (anti, racemic) (43%): amorphous solid. H NMR (600 MHz,
CD3CN, 1.94 ppm, +25 °C): δ 2.30 (3H, s), 2.31 (3H, s), 2.33 (3H,
s), 7.33−7.42 (11H, m), 7.46 (1H, d, J = 7.63 Hz). 13C NMR (150.8
MHz, CD3CN, 118.2 ppm, +25 °C): δ 17.4 (CH3), 17.5 (CH3), 17.7
(CH3), 128.0 (1 CH), 128.1 (1 CH), 128.15 (1 CH), 129.59 (1 CH),
3378
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The Journal of Organic Chemistry
Article
normal mode35 validated the identification of the transition states. The
energy values of the barriers listed in Table 1 derive from total
electronic energies. In general, these give the best fit with experimental
DNMR data,36 and for this reason, the computed values have not been
corrected for zero-point energy contributions or other thermodynamic
parameters. This approach avoids artifacts due to the ambiguous
choice of the adequate reference temperature and from the idealization
of low-frequency vibrators as harmonic oscillators.37
ECD and VCD Simulations. The ECD spectra of 2a, 2c, and 5
were simulated by means of TD-DFT calculations. The electronic
excitation energies and rotational strengths have been calculated in the
gas phase using the geometries obtained at the B3LYP/6-31G(d) level
with the CAM-B3LYP functional that includes long-range correction
using the Coulomb attenuating method.38 All the calculations
employed the 6-311++G(2d,p) basis set because this basis set has
been widely used in this kind of calculation and proved to be
sufficiently accurate at a reasonable computational cost. Rotational
strengths were calculated in both length and velocity representation,
the resulting values being very similar (differences below 5%). For this
reason, the errors due to basis set incompleteness should be very small,
or negligible.39 The simulated spectra were obtained using the first 50
calculated transitions (lowest wavelength about 165 nm) and applying
a 0.5 eV line width. The calculated VCD spectra were obtained by
frequency calculations at the B3LYP/6-31+G(2d,p) level, using the
optimized geometries obtained at the B3LYP/6-31G(d) level.
Patent JP 0187,649, 1989. (f) Osturek, R.; Wingler, F.; Geyev, O.
Patent DE 3,729,457, 1989.
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Novi, M.; Pierini, M.; Tavani, C.; Villani, C. J. Org. Chem. 2002, 67,
1663−1668.
(13) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M. Tetrahedron
2004, 60, 4451−4458.
(14) Lunazzi, L.; Mazzanti, A.; Minzoni, M.; Anderson, J. E. Org. Lett.
2005, 7, 1291−1294.
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10062−10066.
(16) (a) Lunazzi, L.; Mazzanti, A. J. Am. Chem. Soc. 2004, 126,
12155−12157. (b) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org.
Chem. 2007, 72, 5391−5394. (c) Lunazzi, L.; Mancinelli, M.;
Mazzanti, A. J. Org. Chem. 2008, 73, 2198−2205. (d) Lunazzi, L.;
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(17) The 13CH coupling constants of the methyl groups in 2a and 2b
are both equal to 127.5 Hz.
ASSOCIATED CONTENT
■
S
* Supporting Information
Kinetics of the thermal equilibration of 1−3; enantioselective
HPLC traces of 2 and 5; experimental and simulated VT 13C
NMR spectra of 3 and 4; experimental and simulated ECD and
VCD spectra of 3; NOE spectra of 5; ECD spectra of the
enantiomeric pairs of 2, 3, and 5; crystallographic data of 4; 1H
and 13C NMR spectra and DFT computational data of 1−5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The computed averaged interproton methyl distances are 4.08 Å
in the case of the syn (meso) 2b and 6.43 Å in the case of the anti
(racemic) 2a. As required when dealing with NOE experiments, these
averages were obtained by taking into account the 6th root, according
to Claridge, T. D. W. High Resolution NMR Techniques in Organic
Chemistry; Pergamon: Oxford, UK, 1999; p 303. (If the 6th root is not
applied, the corresponding averaged distances become 4.84 and 6.69
Å, respectively.)
(19) Owing to the unresolved long-range couplings with fluorine of
CF3, the ortho signals are too broad to display the multiplicity expected
for the J coupling with the meta hydrogens and thus appear as single
signals.
(20) (a) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2011,
76, 1487−1490. (b) Mazzeo, G.; Giorgio, E.; Zanasi, R.; Berova, N.;
Rosini, C. J. Org. Chem. 2010, 75, 4600−4603. (c) Pescitelli, G.; Di
Pietro, S.; Cardellicchio, C.; Annunziata, M.; Capozzi, M.; Di Bari, L. J.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andrea.mazzanti@unibo.it.
Notes
The authors declare no competing financial interest.
̀
Org. Chem. 2010, 75, 1143−1154. (d) Jacquemin, D.; Perpete, E. A.;
ACKNOWLEDGMENTS
■
Ciofini, I.; Adamo, C.; Valero, R.; Zhao, Y.; Truhlar, D. G. J. Chem.
Theory Comput. 2010, 6, 2071−2085. (e) Gioia, C.; Fini, F.; Mazzanti,
A.; Bernardi, L.; Ricci, A. J. Am. Chem. Soc. 2009, 131, 9614−9615.
(f) Stephens, P. J.; Pan, J. J.; Devlin, F. J.; Cheeseman, J. R. J. Nat.
Prod. 2008, 71, 285−288. For reviews, see: (g) Bringmann, G.;
Bruhn, T.; Maksimenka, K.; Hemberger, Y. Eur. J. Org. Chem. 2009,
2717−2727. (h) Bringmann, G.; Gulder, T. A. M.; Reichert, M.;
Gulder, T. Chirality 2008, 20, 628−642. (I) Berova, N.; Di Bari, L.;
Pescitelli, G. Chem. Soc. Rev. 2007, 36, 914−931.
Financial contribution was received from the University of
Bologna (RFO funds 2009 and 2010).
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