Spontaneous generation of chirality and chiroptical spectra of N-nitroso-2,4-diaryl-3-azabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1016/j.tetasy.2012.02.012

The crystal structures of several bicyclic N-nitrosamines indicate that they crystallize in the chiral (Sohncke) space group P2₁2 ₁2₁ as conglomerates. This allows the resolution of these compounds by manual picking of the

Full text of DOI:10.1016/j.tetasy.2012.02.012

Tetrahedron: Asymmetry 23 (2012) 278–283
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Spontaneous generation of chirality and chiroptical spectra of
N-nitroso-2,4-diaryl-3-azabicyclo[3.3.1]nonanes
a
a
b
a,
⇑
´
Teresa Olszewska , Maria J. Milewska , Maria Gdaniec , Tadeusz Połonski
a
´
Department of Chemistry, Technical University, 80-233 Gdansk, Poland
b Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The crystal structures of several bicyclic N-nitrosamines indicate that they crystallize in the chiral (Sohn-
cke) space group P212121 as conglomerates. This allows the resolution of these compounds by manual
picking of the enantiomorphous crystals. The optical activity of the single crystals was confirmed by their
CD spectra taken in KBr disks. The absolute configurations of the title nitrosamines were assigned by
crystallographic measurements and by a comparison of their CD spectra with those of a reference com-
pound resolved by classical methods. The observed Cotton effect signs, corresponding to the n–p⁄ tran-
sition, were correlated with the helicity of the inherently chiral nitrosamine chromophore.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 January 2012
Accepted 15 February 2012
Available online 14 March 2012
1. Introduction
N-Nitrosamines have been extensively investigated over the
last three decades because of their strong carcinogenic and muta-
genic properties.1 They have also found synthetic applications as
intermediates for the preparation of various N,N-bonded function-
alities.2 The restricted rotation about the N–N bond brought about
by the polar resonance structure >N+@N–Oꢀ leads to many unusual
stereochemical features in these compounds. A weak long-wave-
length absorption makes the N-nitrosamino chromophore an
attractive model for spectroscopic studies.2a,3 Their chiroptical
properties have been the subject of many investigations in the last
few years.4
N
N
N
N
O
O
I
ent-I
Scheme 1.
phenomenon that deserves considerable attention due to it being
one of the simplest and least expensive methods for the prepara-
tion of enantiomerically pure compounds. It may also have
important implications for the prebiotic origin of chirality8 or
so-called ‘absolute’ asymmetric synthesis.9
The rigid 3-azabicyclo[3.3.1]nonane system upon N-substitu-
tion with a nitroso group loses its symmetry and becomes chiral.
The conversion between the two enantiomers occurs by the rota-
tion of the nitroso group (Scheme 1).
Herein, we report the solid state CD spectra taken in KBr disks
and correlate the observed Cotton effect signs with molecular
chirality. In addition, we have resolved the chiral amine 6a into
its enantiomers and converted them into nitrosamines 6b. This
allowed us to study their solid state and solution CD spectra in
relation to those of 1b–4b. Due to the close relationship between
the nitrosamine and nitramine chromophores,10 nitrosamine 6b
was oxidized into N-nitramine 6c whose chiroptical spectra were
examined in order to gain further insight into the nature of the
optical activity of the title compounds.
The title N-nitrosamines 1b–3b owe their chirality solely to the
restricted rotation about the N–N bond. In contrast, compounds
4a,b and 6a,b are chiral due to the desymmetrization of the
bicyclic skeleton by methyl substitution at C-1. Our X-ray
crystallographic studies and a literature survey revealed that the
N-nitrosamines 1b–4b crystallize in the chiral space group
P212121.5,6 Usually this means that the racemic mixture forms a
conglomerate; that is, a mechanical mixture of homochiral crystals
wherein each single crystal is comprised of only one enantiomer.7
Thus, the spontaneous generation of chirality occurs during the
2. Results and discussion
crystallization. This is
a relatively rare and unpredictable
2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-ones 1a–5a were pre-
pared by a Mannich condensation of substituted benzaldehydes
⇑
Corresponding author. Tel.: +48 58 3471528; fax: +48 58 3472694.
E-mail address: tadpol@chem.pg.gda.pl (T. Połon´ ski).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.012

T. Olszewska et al. / Tetrahedron: Asymmetry 23 (2012) 278–283
279
O
R1
R2
Ph
Ph
N
X
Ar
Ar
N
X
6a
X = H
6b X = NO
6c X = NO2
F
F
X = H
X = NO
1a
1b
R1= R2= Me,
R1= R2= H,
R1= R2= H,
Ar =
Ar =
Ar =
2a
2b
Me
OMe
OMe
3a
4a
5a
3b
4b
R1= Me, R2 = H, Ar =
R1= Me, R2 = H, Ar = Ph
with the appropriate cyclohexanones and ammonium acetate
according to the literature.5,11 Amine 6a was obtained by a
Wolff-Kishner reduction of ketone 5a,5 and then resolved into its
enantiomers by crystallization of the diastereomeric salts with
(S)-(+)-mandelic acid man. Two crystalline forms of the salt,
6aH+ Åmanꢀ as the major product, and (6aH+Åman–)2 man as the
Å
minor product, were isolated and the amine’s absolute configura-
tion was determined from their X-ray structures revealing the
(1R)-configuration of the (–)-enantiomer in both crystal forms.
The optically active amine was obtained with 93% ee after two
crystallizations of the salt from chloroform. The nitrosation of the
amines with HNO2 gave nitrosamines 1b–4b and (+)-6b. The
oxidation of compound 6b with trifluoroperacetic acid in CH2Cl2
was carried out according to a procedure reported by Emmons12
to afford the N-nitramine (+)-6c.
Figure 1. Molecular structure of E-1b. Displacement ellipsoids are drawn at the 30%
The X-ray diffraction studies of N-nitrosamines 1b–4b showed
that the bicyclic skeleton adopts a twin-chair conformation stabi-
lized by the aryl substituents at the equatorial positions (Fig. 1).
The single crystals obtained by crystallization of the racemic
compounds 1b–4b showed that all of them crystallized in the chi-
ral space group P212121 indicating that a spontaneous resolution
was achieved. The crystal structure of 1b revealed that this com-
pound forms homochiral crystals with each single crystal contain-
ing only one enantiomer. On the other hand, the structures of
2b–4b showed that the nitroso group exhibits minor disorder
assuming two orientations; however, the occupancy factors of
the minor orientation are smaller than 0.120(3) in each case, thus
indicating a significant preference of one enantiomer. The chirality
of the above nitrosamines, resolved by a simple crystallization, was
confirmed by their CD measurements.
The title compounds are rare examples of non-planar nitrosa-
mine systems that, in contrast to the small ring compounds such
as N-nitrosoaziridines,13 are stable at room temperature, which
makes them valuable models for spectroscopic investigation. The
non-planarity of the nitrosamino chromophore is caused by the
so called pseudoallylic A(1,3) strain, which in turn is caused by
the strong steric interaction of the nearly coplanarly located two
C atoms of the equatorial aryl substituents and the NNO group.5,14
probability level.
In order to avoid this strain, the molecules increase the pyramidal
character of the amino nitrogen driving the NO group from the
plane formed by the amino N-atom and the C-1 carbons of the aryl
substituents. This was confirmed by the X-ray structures of 1b–4b
and 6b, which revealed the displacement of the N-3 atom from the
plane formed by the three neighboring atoms by 0.226–0.283 Å. A
weakening of the nN–pNO conjugation in the non-planar nitrosami-
no group results in a decreased barrier to the N–N rotation. In the
case of 1b–4b the corresponding activation energies are of the or-
der of 13 kcal/mol and are almost half of those reported for simple
nitrosamines (23–25 kcal/mol).5,15 In effect, compounds 1b–3b
racemize instantly upon dissolution. Thus, their CD spectra can
only be measured in the solid state. In contrast, nitrosamine 4b,
containing an asymmetrically substituted skeleton, is stereochem-
ically stable in solution. The distortion of the chromophore from
planarity results in a bathochromic shift of the n–p electronic tran-
sition16 in the UV spectra of 1b–4b and 6b while the title com-
pounds absorb near 410 nm in non-polar solvents as well as in
the solid state, that is, at approximately 50 nm longer wavelengths
than simple nitrosamines. The CD spectra of the compounds stud-
ied are collected in Table 1. The observed nitrosamine n–p Cotton

280
T. Olszewska et al. / Tetrahedron: Asymmetry 23 (2012) 278–283
Table 1
Circular dichroism (CD) data
we performed X-ray crystallographic analysis of three small pieces,
that had been carefully cut from a large single crystal of this
nitrosamine, and measured the solid state CD of the residual part.
The absolute configuration was determined on the basis of the
weak anomalous signals of the N, O, and F atoms. This resulted
in a consistent indication of the E-configuration (geometric enanti-
omerism)18 for all three pieces, thus minimizing the problem of
possible racemic twinning of the crystal (see Experimental).
A sample of E-1b showed a negative Cotton effect at 432 nm
and a positive one at 378 nm; hence the configuration of the
remaining nitrosamines crystallizing in the chiral space group
can be assigned by comparison of their solid state CD spectra with
Compd Solvent
CD k, nm ([Q])a
b
1b
2b
3b
4b
KBr
KBr
KBr
Dioxan
KBr
433 (ꢀ2430), 372 (1040), 296 (2470)
b
448 (240), 403 (–2230), 309 (2370)
b
440 (80), 400 (–930)
435 (ꢀ227), 387 (283) 438 (–520), 392 (1460)
b
6b
MeOH
KBr
425 (776), 375 (–1790), 263 (–6500) 430 (780), 385 (–
b
1200)
6c
MeOH
294 (–1180), 243 (18800)
Molecular ellipticity in deg cm2 dmolꢀ1
.
a
b
Approximate experimental values determined by considering the weight con-
centration (KBr density 2.75 g cmꢀ3).
those of 1b in the region of the nitrosamine n–p transition. These
assignments were also confirmed by the solution and solid state
CD measurements for 6b. This compound, which has a (1R)-config-
uration, showed a sequence of the positive and negative CEs at 425
and 380 nm, respectively in CH2Cl2 solution and the solid state.
According to the 1H NMR spectrum, the anti-rotamer predominates
in the conformational equilibrium of 6b in solution (the syn/anti ra-
tio is 32:78), whereas in the solid state it is the only stereoisomer.
In this case, the (1R)-configuration of the molecule with an anti-
orientation of the nitroso group is equivalent to the Z-configuration
of the geometric enantiomers of 1b–3b. The observed CEs are
rather strong, which points to an inherent chirality of the non-pla-
nar nitrosamine chromophore. The only exception is the solution
spectrum of 4b that showed a low magnitude of the CEs, appar-
ently due to the almost equal population of the two rotamers
(syn/anti 46:54) showing an opposite helicity of the chromophore.
effects (CEs) have a bisignate form in the solid state and also in
solution, as in the case of 6b (Figs. 2 and 3).
The CD spectra of 1b and 2b revealed two additional CD bands
near 300 and 270 nm with a pronounced fine structure. The last
band was also evident in the solution spectrum of 6b. The
300 nm band can be assigned unequivocally to the ketone n–
p
electronic transition, whereas the second one probably corre-
sponds to the aromatic 1Lb transition, since the strong nitrosamine
p–p absorption occurs at shorter wavelengths near 230 nm, which
is usually structureless.17 In order to establish the absolute
configuration of 1b and correlate it with the observed CE signs,
Thus, the n–p CE sign of the title nitrosamines can be simply
predicted by a simple helicity rule: the chromophore twisted in
the P sense, as in 1b (the C–N–N@O torsion angle is 9.8o), should
lead to a sequence of positive and negative CEs at higher and lower
wavelengths. On the other hand, M chirality, as in 6b (the C–N–
N@O torsion angles in two independent molecules in the unit cell
are of –9.4 and –8.6o), results in oppositely signed CEs being
observed in solution as well as in the solid state.
The cause of the bisignate character of the CD curves in the re-
gion of the nitrosamine n–p transition is not clear. A similar form
of the solution spectra, discussed earlier, in some N-nitrosopiperi-
dines has been attributed to the equilibria of two or more ring
conformers contributing to the CE with opposite signs.4b This is
obviously impossible in the case of rigid bicyclic compounds,
particularly in the solid state. In some cases, the bisignate CD
may be attributed to a vibronic coupling effect.19 According to
Dekkers and Closs, a difference in the equilibrium geometry
between the ground and excited state of the molecule enables
molecular vibrations to generate two oppositely signed compo-
nents to the CE.20 This seems to be a reasonable explanation for
the compounds with a non-planar nitrosamine chromophore,
which may easily change the geometry around the pyramidal ami-
no nitrogen during the excitation.
Figure 2. CD and UV–vis (lower curve) spectra of 1b and 3b measured in KBr disks.
The chromophore in nitramine 6c is also deviated from planar-
ity for the same reasons as the related nitrosamines. However in
this case, it remains inherently symmetric (Cs) as shown by the
crystal structure (the CNNO torsion angles are of 19.3 and –20.3o
in the A molecule and 20.1 and –18.6o in the molecule B). Thus,
the CE at 294 nm in the region of the nitramine n–
is relatively weak and monosignate, whereas the strong CD near
p
transition10a,21
Ph
Ph
O
N
N
250 nm corresponds to overlapping nitramine
p–p and aromatic
6b
1Lb transition (Fig. 4).
3. Conclusion
In conclusion, we have found that some easily accessible 2,4-
diaryl-3-azabicyclo[3.3.1]nonan-9-ones crystallize as conglomer-
Figure 3. CD and UV–vis (lower curve) spectra of 6b taken in methanol.

T. Olszewska et al. / Tetrahedron: Asymmetry 23 (2012) 278–283
281
J = 7.3 Hz, 2H), 7.19 (m, 4H), 4.59 (s, 2H), 3.02 (m, 1H), 2.51 (s,
2H), 2.35 (s, 6H), 1.99 (m, 1H), 1.78 (m, 2H), 1.61 (s, 1H), 1.44
(m, 1H); 13C NMR (CDCl3) d 217.8, 139.0, 134.8, 130.8, 127.2,
125.9, 61.3, 50.7, 29.3, 21.0, 19.1; Anal. Calcd for C22H25NO (319):
C, 82.7; H, 7.9; N, 4.4. Found: C, 82.8; H, 7.8; N, 4.5.
Ph
Ph
N
NO2
4.3. 1-Methyl-2,4-bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]
nonan-9-one 4a
6c
Obtained in a manner similar to that of compound 2a; mp 143–
144 °C (toluene–heptane); 1H NMR (CDCl3) d 7.48 (d, J = 8.8 Hz,
2H), 7.43 (d, J = 8.8 Hz, 2H), 6.92 (m, 4H), 4.34 (d, J = 2.9 Hz, 1H),
3.89 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.16 (m, 1H), 2.51 (s, 1H),
2.08 (m, 1H), 1.97 (m, 1H), 1.82 (s, 1H), 1.72 (m, 1H), 1.45 (m,
2H), 0.80 (s, 3H); 13C NMR (CDCl3) d 218.1, 159.2, 158.8, 133.4,
132.0, 130.0, 127.8, 113.8, 113.3, 64.4, 55.2, 54.6, 50.9, 29.0, 21.4,
20.3; Anal. Calcd for C23H27NO3 (365): C, 75.6; H, 7.5; N, 3.8. Found:
C,75.5; H, 7.5; N, 3.8.
Figure 4. CD and UV–vis (lower curve) spectra of 6c taken in methanol.
4.4. (1R)-1-Methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonane 6a
ates and therefore by picking a suitable crystal, we were able to
measure their chiroptical spectra. Simple crystallization is obvi-
ously the most economical procedure for obtaining chiral com-
Racemic amine 6a (5.1 g, 15 mmol) and (+)-mandelic acid
(2.3 g, 15 mmol) were dissolved in hot toluene (25 ml). The precip-
itated salt was recrystallized from hot toluene. The crystalline salt
was treated with 10% aqueous solution of NaOH and extracted
with benzene. After evaporation of the solvent the residue was
pounds. However, the spontaneous resolution is not
a very
frequent phenomenon, since most compounds show a great ten-
dency to crystallize in centrosymmetric space groups. The N-nitro-
so-2,4-diaryl-3-azabicyclo[3.3.1]nonanes derived from symmetric
amines rapidly racemize in solution and therefore their CD spectra
must be taken in the solid state. A pyramidal character of the ami-
no nitrogen caused by the pseudoallylic A(1,3) strain in these com-
pounds causes an inherent chirality of the NNO chromophore that
leads to strong bisignate Cotton effects in their CD spectra. The ob-
recrystallized from methanol to obtain 1.6 g of the product, mp
111–112 °C (racemate lit.5 mp 128–129 °C); [
a]
D
= +26.2 (c 4,
22
C6H6); ee 93%.
4.5. N-Nitroso-2,4-bis(2-methylphenyl)-3-azabicyclo[3.3.1] nonan
-9-one 2b
served n–p CD signs are governed by the helicity of the non-planar
nitrosamine group.
To a solution of amine 2a (1.60 g, 5 mmol) in chloroform
(10 mL) were added concentrated hydrochloric acid (1.5 mL) and
water (1.5 mL), and while stirring, solid NaNO2 (0.84 g, 12 mmol)
was added in portions over 0.5 h. The stirring was continued for
another 0.5 h. The organic layer was washed with water and satu-
rated NaHCO3 and dried (Na2SO4). After evaporation of the solvent,
the residue was crystallized from toluene–heptane: yield 1.45 g
(78%); mp 197–198 °C dec; 1H NMR (CDCl3) d 7.8–7.4 (br, 2H),
7.26 (m, 6H), 5.62 (br, 2H), 2.92 (s, 2H), 2.42 (s, 6H), 2.28 (m,
1H), 1.77 (m, 4H), 1.47 (m, 1H); 13C NMR (CDCl3) d 213.3, 135.6
(br), 133.4 (br), 131.5, 127.9, 127.4, 125.9, 64.2 (br), 48.2, 30.2,
19.2, 18.4; Anal. Calcd for C22H24N2O2 (348): C, 75.8; H, 6.9; N,
8.0. Found: C, 75.5; H, 7.0; N, 8.0.
4. Experimental
4.1. General
Compounds 1a, 3a, 5a, and 1b were prepared as described pre-
viously.5,11 The ee of the amine (+)-6a was assigned by 1H NMR
measurements with the use of (R)-(+)-a-methoxy-a-(trifluoro-
methyl)phenylacetic acid as the chiral solvating agent. 1H and
13C NMR spectra were obtained on a Varian Unity Plus spectrome-
ter at 500 and 125 MHz, respectively. Deuterated solvents were
used as the internal lock for 1H and 13C NMR. The solid state CD
spectra were taken with freshly prepared KBr disks and recorded
with a Jasco J-715 dichrograph. A mixture of 2–5 mg of the sample
and 250 mg of dried KBr was ground and formed into a disk
0.5 mm thick and with radius of 15 mm. The disk was rotated
around the optical axis and the CD recordings were made for sev-
eral positions in order to check the reproducibility of the spectra.
Caution: All nitrosamines are potential chemical carcinogens, and
special care should be taken in the handling and disposal of these
substances.22
4.6. N-Nitroso-2,4-bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]
nonan-9-one 3b
Obtained in a manner similar to that of compound 2b; mp 166–
169 °C dec (CH2Cl2–MeOH); 1H NMR (CDCl3) d 7.40–7.10 (br, 4H),
6.96 (m, 4H), 5.42 (br, 1H), 3.83 (s, 6H), 2.83 (m, 2H), 1.99 (m,
1H), 1.75 (m, 1H), 1.70 (m, 2H), 1.18 (m, 1H); 13C NMR (CDCl3) d
213.1, 158.7, 130.2, 129.6 (br), 126.4 (br), 114.1, 63.5 (br), 55.2,
51.5, 29.9, 18.1; Anal. Calcd for C22H24N2O4 (380): C, 69.5; H, 6.4;
N, 7.4. Found: C, 69.4; H, 6.5; N 7.1.
4.2. 2,4-Bis(2-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
2a
4.7. N-Nitroso-1- methyl-2,4-bis(4-methoxyphenyl)-3-azabicyclo
[3.3.1]nonan-9-one 4b
A solution of ammonium acetate (1.9 g, 25 mmol), o-tolualde-
hyde (6.0 mL, 50 mmol) and cyclohexanone (3.5 mL, 35 mmol) in
methanol (25 mL) was left to stand for 24 h at room temperature.
The precipitated crystals were filtered, washed with methanol, and
recrystallized from toluene-heptane: yield 3.1 g (35%); mp 225–
Obtained in a manner similar to that of compound 2b; mp 156–
159 °C dec (CH2Cl2–MeOH); 1H NMR (CDCl3) d 7.44 (br, 2H), 7.10
(br, 2H), 6.95 (m, 4H), 5.29 (br, 1H), 5.05 (br, 1H), 3.84 (s, 3H),
3.81 (s, 3H), 2.93 (m, 1H), 2.24 (m, 1H), 1.97 (m, 1H), 1.73 (m,
2H), 1.47 (m, 2H), 1.08 (s, 3H); 13C NMR (CDCl3) d 214.3, 159.5,
226 °C; 1H NMR (CDCl3)
d 8.00 (d, J = 7.8 Hz, 2H), 7.32 (t,

282
T. Olszewska et al. / Tetrahedron: Asymmetry 23 (2012) 278–283
159.1, 130.2, 129.6 (br), 129.2, 126.4 (br), 114.3, 114.1, 74.5 (br),
65.5 (br), 55.5, 51.3, 50.0, 37.6, 30.5, 21.8, 19.5; Anal. Calcd for
Crystal data for C22H20F4N2O2 1b: orthorhombic, space group
P212121, a = 7.8736(1), b = 11.3831(1), c = 21.7311(1) Å, V =
1947.67(3) Å3, Z = 4, k = 1.54184 Å, T = 293 K, number of measured
reflections 155721, Rint = 0.0434, R1 = 0.0300, wR2 = 0.0866 for
C23H26N2O4 (394): C, 70.0; H, 6.6; N, 7.1. Found: C, 69.8; H, 6.6;
N, 7.0.
4072 independent reflections with I > 2
x = ꢀ0.01(10).
r
(I), Flack parameter24
4.8. (1R)-N-Nitroso-1-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]
nonane 6b
Crystal data for C22H24N2O2 2b: orthorhombic, space group
P212121, a = 6.9909(1), b = 8.0891(2), c = 33.0085(7) Å, V =
1866.63(7) Å3, Z = 4, k = 1.54184 Å, T = 293 K, number of measured
reflections 41905, Rint = 0.0207, R1 = 0.0354, wR2 = 0.0957 for 3897
Obtained in a manner similar to that of compound 2b; mp 173–
174 °C (CH2Cl2–MeOH) (racemate lit.5 mp 139 °C); [ 22 = +36.5 (c
a]
D
2.3, C6H6).
independent reflections with I > 2r(I). The absolute structure could
not be reliably assigned as the Flack parameter24 s.u. value was too
high [x = 0.0(3)]. The nitroso group that is disordered over two
positions was refined with restraints imposed on its geometry.
The occupancy factor of the minor position is 0.119(2).
4.9. (1R)-N-Nitro-1-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]
nonane 6c
To 80% of hydrogen peroxide (0.4 mL) suspended in 5 mL of
methylene chloride (5 mL) with stirring was added trifluoroacetic
anhydride (2 mL) under a reflux condenser. After the vigorous
reaction ceased, a solution of peroxytrifluoroacetic acid (2.5 mL)
was added dropwise to nitrosoamine 6b (0.64 g, 2 mmol) in meth-
ylene chloride (10 mL). The reaction mixture was left to stand
overnight at room temperature. The organic layer was washed
with water and saturated NaHCO3 and dried (Na2SO4). After evap-
oration of the solvent, the residue was subjected to column chro-
matography on silica gel, and elution with CHCl3 gave 0.35 g
(52%) of the product crystallized from CH2Cl2–MeOH; mp 180–
Crystal data for C22H24N2O4 3b: orthorhombic, space group
P212121, a = 7.5779(2), b = 10.8891(3), c = 22.9360(6) Å, V =
1892.60(9) Å3, Z = 4, k = 1.54184 Å, T = 293 K, number of measured
reflections 43543, Rint = 0.0467, R1 = 0.0307, wR2 = 0.0805 for 3822
independent reflections with I > 2r
(I), Flack parameter24 x =
ꢀ0.04(17). The nitroso group that is disordered over two positions
was refined with restraints imposed on its geometry. The occu-
pancy factor of the minor position is 0.073(2).
Crystal data for C23H26N2O4 4b: orthorhombic, space group
P212121, a = 8.1311(1), b = 11.3597(1), c = 22.1609(2) Å, V =
2046.93(4) Å3, Z = 4, k = 1.54184 Å, T = 293 K, number of measured
reflections 15561, Rint = 0.0175, R1 = 0.0323, wR2 = 0.0895 for 4235
181 °C dec (½a 2D2
ꢁ
+68.6 (c 3, C6H6); 1H NMR (CDCl3) d 7.60–7.25
(complex m, 10 H), 5.34 (d, J = 6.8 Hz, 1H), 4.88 (s, 1H), 2.64 (m,
1H), 1.91 (m, 1H), 1.74 (m, 2H), 1.30 (m, 1H), 1.24 (m, 2H), 1.14
(m, 1H) 1.10 (s, 3H), 0.95 (m, 1H); 13C NMR (CDCl3) d 141.3,
139.8, 128,5, 128.0, 127.0, 126.5, 124.4, 76.5, 69.2, 38.8, 35.8,
35.5, 33.9, 30.8, 26.4, 19.7; Anal. Calcd for C21H24N2O2 (394): C,
75.0; H, 7.2; N, 8.3. Found: C, 74.7; H, 7.2; N, 8.3.
independent reflections with I > 2r(I). The absolute structure could
not be reliably assigned as the Flack parameter24 value was
x = 0.39(18). The nitroso group that is disordered over two
positions was refined with restraints imposed on its geometry.
The occupancy factor of the minor position is 0.109(3).
Crystal data for C21H24N2O 6b: monoclinic, space group P21,
a = 11.483(2), b = 7.6774(1), c = 11.996(2) Å, b = 96.50(3)°, V =
1768.6(6) Å3, Z = 4, k = 1.54184 Å, T = 293 K, number of measured
reflections 3172, Rint = 0.0239, R1 = 0.0334, wR2 = 0.0929 for 3042
4.10. X-Ray crystal structure analyses
The X-ray intensity data were collected with a four-circle KM4
independent reflections with I > 2r(I).
diffractometer using Mo K
Cu K radiation 6b and with an Oxford Diffraction SuperNova dif-
fractometer using Cu K
radiation 1b–4b, 6c, bis[6aH+-(S)-(+)-
a
radiation [6aH+-(S)-(+)-mandelate] or
Crystal data for C21H24N2O2 6c: monoclinic, space group P21,
a = 12.3866(1), b = 12.922(3), c = 19.2324(1) Å, b = 94.536(1)°,
V = 1823.21(3) Å3, Z = 4, k = 1.54184 Å, T = 294 K, number of mea-
sured reflections 85585, Rint = 0.0298, R1 = 0.0331, wR2 = 0.0919
a
a
mandelate]-mandelic acid. The crystal structures were solved by
direct methods with SHELXS9723 and refined by full-matrix least-
squares SHELXL97.23 All hydrogen atoms were refined as riding
on their carriers and their displacement parameters were set equal
to 1.5Ueq(C) for the methyl groups and 1.2Ueq(C) for the remaining
H atoms.
for 7297 independent reflections with I > 2r(I). For this compound
with known absolute configuration the Flack parameter24 value
was x = 0.09(14)
Crystal data for C21H26NꢂC8H7O3 6aH+-(S)-(+)-mandelate: ortho-
rhombic, space group P212121, a = 10.045(2), b = 10.990(2),
c = 21.689(4) Å, V = 2394.3(8) Å3, Z = 4, k = 0.71073 Å, number of
measured reflections 2166, T = 293 K, R1 = 0.0432, wR2 = 0.1020
Two factors could influence the enantiopurity of the crystals
studied, the disorder of the NNO group and racemic twinning.
Therefore a special care was taken in order to identify any possible
signs of disorder of the nitroso groups by analyzing the final elec-
tron-density difference maps and the shape of the displacement
ellipsoids of the nitrosamine N and O atoms. In the case of 1b,
where due to the presence of F atoms, the strongest anomalous sig-
nal could be obtained, in order to rule out the possibility of racemic
twinning, three data sets with a very large redundancy were col-
lected from three small crystals cut from a larger well-shaped
specimen. In each case, a nearly identical value of the Flack param-
eter was obtained with an s.u. value of 0.10 indicating the same
absolute structure over the crystal. Moreover the fourth data set
was collected from a different crystal taken from the same crystal-
lization batch for which the opposite absolute structure was deter-
mined based on the value of the Flack parameter24 x = 0.05(11).
Based on the above data, despite a rather high s.u. value of the
Flack parameter, enantiopurity of the crystals of 1b was assumed.
In turn, for the crystals of 2b and 4b, X-ray diffraction data did not
allow us to rule out the possibility of their twinning by inversion.
for 2166 independent reflections with I > 2r(I). The absolute con-
figuration of 6aH+ determined as 1R relative to the known config-
uration of (S)-(+)mandelate.
Crystal data for 2(C21H26N)ꢂ2(C8H7O3)ꢂ(C8H8O3) bis[6aH+-(S)-
(+)-mandelate]-mandelic acid: monoclinic, space group P21, a =
10.1226(2), b = 20.7144(5), c = 13.9086(3) Å, b = 105.756(2)°,
V = 2806.83(11) Å3, Z = 4, k = 1.54178 Å, T = 296 K, number of mea-
sured reflections 21764, Rint = 0.0180, R1 = 0.0469, wR2 = 0.1323 for
10397 independent reflections with I > 2r
(I), Flack parameter24
x = ꢀ0.04(16). The absolute configuration of 6aH+ was determined
as (1R)-relative to the known configuration of (S)-(+)-mandelate.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 857277–857284. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].

T. Olszewska et al. / Tetrahedron: Asymmetry 23 (2012) 278–283
283
Compounds; Wiley: New York, 1994. Chapter 7.2.; (c) Perez-Garcia, L.;
Amabilino, D. Chem. Soc. Rev. 2002, 31, 342.
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