Chiroptical and conformational properties of (R)-1-phenylethylamine derivatives of persubstituted benzene

Article abstract of DOI:10.1016/S0957-4166(99)00171-8

Chiral derivatives of 2,4,5,6-tetrachloro-1,3-dicyanobenzene 1 with one, two and three (R)-1-phenylethylamino ((R)-PEA) units 2-4 are prepared and their chiroptical and conformational properties discussed on the bases of the UV/CD, NMR and MM2 data. High

Full text of DOI:10.1016/S0957-4166(99)00171-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1935–1945
Chiroptical and conformational properties of
(R)-1-phenylethylamine derivatives of persubstituted benzene
Darko Kontrec,a Vladimir Vinkovic´,a Andreja Lesac,a Vitomir Šunjic´ a,∗ and Miklòs Hollòsi b
a‘Ruder Boškovic´’ Institute, POB 1016, HR-10000 Zagreb, Croatia
¯
bEötvös University Budapest, POB 32, H-1117 Budapest, Hungary
Received 6 April 1999; accepted 5 May 1999
Abstract
Chiral derivatives of 2,4,5,6-tetrachloro-1,3-dicyanobenzene 1 with one, two and three (R)-1-phenylethylamino
((R)-PEA) units 2–4 are prepared and their chiroptical and conformational properties discussed on the bases of the
UV/CD, NMR and MM2 data. High polarity of the persubstituted benzene ring leads to peculiar UV and IR spectra
of achiral model compounds 5–7, whereas relatively rigid conformations of the chiral analogues 2–4 are reflected
in the CD spectra. Strong exciton coupling (EC) appears in the CD spectrum of pseudo-C3-symmetric 4; this type
of interaction seems not to be present in the C1-symmetric 2 and C2-symmetric 3. The absence of a molecular
cleft in the chiral structures 2–4 could explain their inability to recognise the enantiomers of some racemates in the
NMR experiment. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Separation of enantiomers by liquid chromatographic (LC) methods on chiral stationary phases (CSPs)
is possible through reversible diastereomeric association between the chiral environment in the column
and the solute enantiomers.1 CSPs are usually classified with respect to their general structural types.
The first group is based on synthetic or natural polymers and is completely and intrinsically homochiral.
The second group consists of chiral selectors of low molecular weight which are bound to a hard,
incompressible matrix, usually silica (brush-type selectors). The latter group of chiral stationary phases
has definite advantages over the former in that chiral selectors can be rationally designed.2 This means
that they can be selected on a rational basis because their enantiorecognition properties can often be
evaluated from NMR studies on solutions containing racemic solute and chiral selectors, or can be
envisaged by computer modelling, based on the well-defined types of chemical interactions. Prompted by
our recent findings that (R)-1-phenylethylamine ((R)-PEA) and other 1-arylethylamines can be used as
∗
Corresponding author. E-mail: sunjic@rudjer.irb.hr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00171-8

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chiral ligands for catalytic complexes,3,4 or as stoichiometric chiral auxiliaries,5 and by the observation
that three chlorine atoms in the persubstituted ring of 2,4,5,6-tetrachloro-1,3-dicyanobenzene 1 can be
regioselectively substituted by thiolate anions,6 we entered this study of model selectors with one, two,
and three (R)-PEA units bound to 1. Herewith we describe structural, conformational and chiroptical
properties of these potential chiral selectors.
2. Results and discussion
Preparation of 2–4 can be carried out in a completely regioselective manner, due to significant
differences in reactivity of the chlorine atoms in 2,4,5,6-tetrachloro-1,3-dicyanobenzene 1 towards
sterically crowded (R)-PEA as a nucleophile. Mono-, di- and trisubstitution at C(4)-, C(4)- and C(6)-, and
C(4)-, C(6)- and C(2)-positions, respectively, can be achieved with over 95% regioselectivity. In order to
get an insight into the chromophoric system, achiral polysubstituted amino-chloro-cyanobenzenes 5–7
have been prepared by acid hydrolysis of 2–4 (Scheme 1).
Scheme 1.
1
2.1. H NMR spectra and MM2 calculations of the preferred conformations
1
Characteristic H NMR signals are presented in Table 1. The NMR signals of the two (R)-PEA
groups in 3 are superimposed, and exhibit small upfield shifts from the corresponding ones in the
monosubstituted derivative 2. This indicates a C2-symmetric arrangement of two (R)-PEA groups on
the time scale of the NMR experiment, in a conformation that does not permit any significant mutual
shielding of the groups in the two (R)-PEA units.
In the compound 4, having pseudo-C3 symmetry, the signals of the third (R)-PEA group are signi-
ficantly shifted upfield relative to the first two, consistent with two phenyl rings being on the same side
of the polysubstituted aromatic ring. If the shielding effect between two phenyl rings were operative, the
upfield shift of the two groups should be higher than the third one on the opposite side of the plane of the
central ring. Since the chemical shifts of only one of the (R)-PEA groups, constitutionally also different

D. Kontrec et al. / Tetrahedron: Asymmetry 10 (1999) 1935–1945
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Table 1
Characteristic 1H NMR data for 2–4 (in CDCl3)
from the former two, are found upfield, they are assigned to those between the two electron-shielding
π-basic cyano groups.
The lowest energy minimum conformation of 2A is found by MM2 to contain a N–H···Cl hydrogen
bond and is characterised by the large (+73°) dihedral angle (ϕ0) defined by C(1)N(10)C(20)C(100) bonds.
It places two aromatic rings in a nearly perpendicular position and C(10)-Me group in the nearly coplanar
position (ϕ00=−167°) relative to the persubstituted aromatic ring. Conformer 2B is characterised by
nearly the same dihedral angles ϕ0 and ϕ00 but higher energy content (∆E 2.18 kcal mol−1) due to the
absence of an N–H···Cl bond, Table 2.
Table 2
Total energy (Etot), selected dihedral angles and (NH···Cl) distance for selected conformation of 2, 3
and 4
The minimum energy conformation of 3A is characterised by nearly equal dihedral angles
(ϕ0 –ϕ0 =71°) and (ϕ001–ϕ002=−169°) between the phenyl rings and the persubstituted benzene ring
1
2
and by a bifurcated N–H···Cl···H–N hydrogen bond (Fig. 1). Such a conformation has C2 symmetry
on the time scale of the NMR experiment. Hydrogen bonding stabilisation of the conformer 3A over 3B
is more pronounced than in 2 and amounts to 2.7 kcal mol−1 per hydrogen bond.
The energy minimum conformation of 4A in Fig. 1 is characterised by the nearly equal dihedral angles
and ϕ0 and ϕ00 for all (R)-PEA units, and a bifurcated hydrogen bond. Such an arrangement of (R)-PEA
units lowers the symmetry, and conformer 4B with higher energy content (∆E 1.7 kcal mol−1) having
only one N–H···Cl bond possesses pseudo-C3 symmetry (C3 symmetry is perturbed by the presence of
a Cl atom instead of a CN group at C(5)).

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Figure 1. Force field calculated stable conformers of 3 and 4. 3A and 3A0 are two projections of the conformer 3A; 4A and 4B
are two energy minima conformers of 4
2.2. UV/IR and CD spectra
UV spectra of polysubstituted achiral derivatives 5–7, comprising the basic chromophoric system, are
presented in Fig. 2 and Table 3.
A characteristic feature of these spectra is the monotonous red shift of the maximum of the first
and strongest band, but non-monotonous change of its intensity. This band is red shifted in 5, which
is obtained by substitution of the chlorine atom at C(4) in 1 for an amino group. In the UV of 6 and 7,
with two and three amino groups, respectively, this maximum is found at 252 nm. The intensity of this
band changes in the order 1≤5∼7≤6, however.
This phenomenon is due to differential degrees of polarisation in the molecules 1 and 5–7, depending
on their overall symmetry and the electronic properties of the substitutents on the ring. Starting compound
1 possesses two planes of symmetry and two different electron-attracting substitutents, chlorine and
the cyano group. Already the first amino group, present in the position C(4), produces polarisation by
favouring the two push–pull resonance forms 5a and 5b (Fig. 3) and eliminates the second (vertical)
symmetry plane, which results in the appearance of the well-defined band at 286 nm.
Two amino groups in 6 can give two resonance forms 6a and 6b (Fig. 3) because of the presence of
the second plane of symmetry, which results in the appearance of the well-separated shoulder at 275 nm.

D. Kontrec et al. / Tetrahedron: Asymmetry 10 (1999) 1935–1945
1939
Figure 2. UV spectra of the compounds 1 and 5–7
Table 3
UV Spectra of the compounds 1–7 (in MeCN)
Compound 7 retains the second plane of symmetry and three amino groups contribute to the three polar
resonance forms, 7a, 7b and 7c, giving the UV a shoulder at 265 nm.
The long-wavelength band for 5 is found at 344 nm; for the compounds with vertical symmetry it
appears at shorter wavelength and is less intense; at 324 nm, 330 nm, and 325 nm for 1, 6 and 7,
respectively.
General features of the IR spectra of 5–7 strongly change in the region 1400–1650 cm−1; its complexity
increases with the number of amino groups. Two strong bands at 1405 cm−1 and 1460 cm−1 for 5 become
closer for 6, at 1455 cm−1 and 1490 cm−1, and even closer for 7, at 1460 cm−1 and 1480 cm−1. This
indicates weakening of the strong N–H···Cl H-bonding in 5. The other two well-defined bands for 5, at
1570 cm−1 and 1640 cm−1, for 6 appear as a sharp band at 1590 cm−1 and multiplet of bands between
1610–1660 cm−1, and for 7 as two multiplets at 1550–1590 cm−1, and 1610–1660 cm−1.
UV and CD spectra of chiral compounds 2–4 are presented in Figs. 4–6.
It can be seen that polar ortho-iminoquinomethane-like resonance structures of 2–4 could explain the
‘anomalies’ in the UV spectra in the same way as discussed for their achiral congeners 5–7. The polar
structures comprise a ‘push–pull ethylene’ type interaction,7 i.e. the resonance structures that perturb
the aromaticity of the benzene ring while maintaining a high degree of conjugation. Phenyl groups at
the stereogenic centres in 2–4 thus face the persubstituted benzene rings at different degrees and with

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Figure 3. Resonance structures of 5–7
different direction polarities. This gives rise to the peculiar change of their UV spectra with degree of
substitution.
Mono-arylamino derivative 2, which possesses C1 symmetry, exhibits a UV spectrum that significantly
differs from those of 3 and 4. It exhibits four distinct bands with the maxima at 206 nm, 247 nm, 298
nm, and 352 nm. The CD spectrum of 2 follows this feature. The four extrema appear: at 214 nm, at ca.
255 nm (actually two local positive maxima are observable at 248 nm and 258 nm), then at 298 nm and
352 nm. Their intensity and zero point position indicate the absence of exciton coupling (EC) between
the 10-phenyl ring of (R)-PEA and the persubstituted aromatic ring.8
Assuming conjugation between the persubstituted benzene ring and the lone pair at the amine nitrogen
in 2, there are two conformers, G1 and G2, which are similar to s-cis- and s-trans-geometric isomers
(Fig. 7). The N–H···Cl bonding leads to the rotamers G1g+ and G1g−, with torsional angles ϕ=73° and

D. Kontrec et al. / Tetrahedron: Asymmetry 10 (1999) 1935–1945
1941
Figure 4. UV and CD spectra of compound 2
Figure 5. UV and CD spectra of compound 3
ϕ=−61°, respectively. G1a+ and G1a−, with s-trans-conformation, differ in the sign of the torsion angle
ϑ for C(1)N(2)C(3)C(4) bonds; ϕ=169° or G1a+, ϕ=−169° for G1a−.
The UV spectrum of 2 is more complex than that of 3. The high intensity of the bands at 247 nm
and 298 nm indicates that the dominant conformers are G1g+ and G1g−. These structures allow charge
transfer interaction between the phenyl ring of (R)-PEA and the cyano group. The complexity of the
spectrum is likely to be caused by the presence of G2 or conformers G1a+, G1a−.
Compound 3 possesses C2-symmetric arrangement, and its UV spectrum exhibits one strong band at
269 nm (ε 1.93×104), ca. 17 nm red shifted from the corresponding band in the UV spectrum of its
achiral congener 6. There is a strong negative CD band at 269.5 nm (∆ε 38.6) and a positive one at the
longer-wavelength side (298.5 nm, ∆ε 9.4). These bands cannot be regarded as a couplet derived from
exciton coupling, due to the same position of the UV and CD bands.10 Its increased intensity may be due
to the presence of one single dominant conformation fixed by both N–H···Cl bonds and charge transfer
interaction between the phenyl and cyano group.

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Figure 6. UV and CD spectra of compound 4
Compound 4 has C1 symmetry; the general shape of its UV spectrum resembles that of 3, but the
intensity of the 270 nm band is ca. 25% higher. In the CD spectrum of 4 there is, however, a strong
positive band at 282 nm (∆ε 27.5) and a more intense negative one at 265.5 nm (∆ε 30.3). This exciton
splitting in the CD spectrum suggests interaction between the third (R)-PEA group (between two cyano
groups) and the charge transfer system of the remaining chromophore of the molecule.
All attempts, using standard NMR techniques,9 to observe enantiorecognition by 2–4 of racemates
listed in the Experimental, failed. Close proximity of the chiral (R)-PEA unit to the persubstituted
benzene ring presumably forms a compact assembly which cannot act as a molecular cleft, indispensable
for multiple interactions between the racemic analyte and chiral compounds 2–4.10
It can be concluded that in the chiral structures 2–4 the core chromophore is a highly polar, persubsti-
tuted aromatic ring. Conformational energy minima correspond to pseudo-C2-symmetric conformer 3A
and pseudo-C3-symmetric 4A, both with bifurcated N–H···Cl···H–N bonds. Strong exciton splitting at
ca. 275 nm in the CD of 4 reflects positive helicity between the (R)-PEA group in the position C(2) and
the polar chromophoric core system.
3. Experimental
1
IR: Perkin–Elmer 297 spectrometer for KBr pellets. H and 13C NMR: Varian Gemini XL 300
spectrometer for CDCl3 solutions, δ in ppm relative to TMS as internal reference, and J in hertz. Melting
point: Electrothermal melting point apparatus. UV: Pay Unicam 8700 Series spectrophotometer. CD:
Jobin–Yvon VI dichrograph, calibrated with epiandrosteron.
Materials: 2,4,5,6-tetrachloro-1,3-dicyanobenzene (1, ≥99% purity) was obtained from Caffaro
S.p.A., R-(+)-, rac-1-phenylethylamine were purchased from Fluka AG. Silica gel for column chromato-
graphy (0.04–0.06 mm), and all solvents were from J. T. Baker Co., p.a. grade.

D. Kontrec et al. / Tetrahedron: Asymmetry 10 (1999) 1935–1945
1943
Figure 7. Conformers and rotamers of 2
3.1. 4-N-((R)-10-Phenylethylamino)-2,5,6-trichloro-1,3-dicyanobenzene 2
Compound 1 (2.00 g, 7.52 mmol) and (R)-PEA (4.56 g, 37.6 mmol) were heated at 100°C until
complete dissolution of 1. The reaction was quenched by rapid cooling, and the reaction mixture applied
onto a silica gel column (100 g). Elution by toluene:n-hexane (1:1) afforded 2.58 g (97%) of pure 2,
slightly-yellow powder, mp 120–121°C (from MeOH); 1H NMR: 1.68 (d, 3H, J=6.4 Hz), 5.76 (dq, 1H,
J1=8.0 Hz, J2=6.4 Hz), 5.90 (d, 1H, J=8.0 Hz), 7.25–7.39 (m, 5H); 13C NMR: 24.58, 54.01, 96.06,
104.02, 112.88, 113.96, 119.89, 125.78, 128.16, 129.16, 139.51, 141.76, 142.17, 148.77. Anal. calcd for
C16H10N3Cl3 (350.62): C, 54.80; H, 2.87; N, 11.98%. Found: C, 54.69; H, 2.67; N, 11.86%.
3.2. 4,6-Di-N-((R)-10-phenylethylamino)-2,5-dichloro-1,3-dicyanobenzene 3
Compound 1 (2.00 g, 7.52 mmol) and (R)-PEA (4.56 g, 37.6 mmol) were heated with MeOH (20
ml) at 100°C oil temperature for 24 h. The solvent was evaporated in vacuo and the reaction mixture
purified on a silica gel column (100 g). Elution by toluene:n-hexane (1:1) afforded 3.15 g (96%) of pure
2, slightly coloured oil. 1H NMR: 1.60 (d, 6H, J=6.7 Hz), 5.34 (d, 2H, J=8.7 Hz), 5.63 (dq, 2H, J1=8.7
Hz, J2=6.7 Hz), 7.24–7.36 (m, 10 H); 13C NMR: 24.50, 53.92, 90.72, 105.48, 115.20, 125.78, 127.75,

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128.89, 142.70, 148.17. Anal. calcd for C24H20N4Cl2 (435.34): C, 66.21; H, 4.63; N, 12.87%. Found: C,
66.20; H, 4.70; N, 12.78%.
3.3. 2,4,5-Tri-N-((R)-10-phenylethylamino)-5-chloro-1,3-dicyanobenzene 4
Compound 1 (0.50 g, 1.9 mmol) and (R)-PEA (2.28 g, 18.8 mmol) were heated at 150°C oil
temperature for 20 h. The reaction mixture was diluted with MeOH (1.0 ml) and applied onto a silica
1
gel column (50 g). Elution by toluene afforded 0.90 g (92%) of pure 2, slightly coloured oil. H NMR:
1.24 (d, 3H, J=6.4 Hz), 1.48 (d, 6H, J=6.4 Hz), 4.73 (d, 1H, J=8.5 Hz), 5.09 (d, 2H, J=8.2 Hz), 5.18
(dq, 1H, J1=8.5 Hz, J2=6.4 Hz), 5.44 (dq, 2H, J1=8.2 Hz, J2=6.4 Hz), 7.23–7.48 (m, 15H); 13C NMR:
22.46, 23.89, 54.12, 54.81, 79.02, 99.07, 117.35, 126.01, 126.30, 127.50, 128.60, 128.69, 142.62, 142.97,
149.59, 155.28. Anal. calcd for C32H30N5Cl (520.01): C, 73.89; H, 5.81; N, 13.46%. Found: C, 73.64;
H, 5.55; N, 13.40%.
3.4. General procedure for preparation of 5–8
Optically inactive compounds 2–4 (1.0 g) were prepared from 1 and racemic (R)-PEA following
the same procedures as described above for the enantiomerically pure compounds. Crude products
were dissolved in MeOH (25.0 ml), and to the ice-cooled solution conc. sulfuric acid (10.0 ml) was
added dropwise. After 10 min stirring at ambient temperature, water (300 ml) was added, the resulting
precipitate collected on filter and washed, first with dil. sodium bicarbonate solution, then with water.
3.4.1. 4-Amino-2,5,6-trichloro-1,3-dicyanobenzene 5
Yield: 435 mg (61.9%), mp 284–285°C. IR: 3420, 3320, 3220, 2220, 1640, 1570, 1540, 1460, 1290,
1
1220, 1210, 1030, 850, 740 cm−1; H NMR (DMSO-d6): 7.91 (s, 2H); 13C NMR (DMSO-d6): 95.43,
100.23, 113.93, 116.96, 139.17, 140.03, 151.96. Anal. calcd for C8H2N3Cl3 (246.47): C, 38.98; H, 0.81;
N, 17.05%. Found: C, 38.73; H, 1.21; N, 16.58%.
3.4.2. 4,6-Diamino-2,5-dichloro-1,3-dicyanobenzene 6
Yield: 469 mg (90.2%), mp 336–338°C. IR: 3460, 3360, 3240, 2220, 1620, 1450, 1350, 1240, 770,
1
740 cm−1; H NMR (DMSO-d6): 6.92 (s, 4H); 13C NMR (DMSO-d6): 86.60, 98.26, 114.78, 139.86,
150.36. Anal calcd for C8H4N4Cl2 (227.05): C, 42.31; H, 1.77; N, 24.68%. Found: C, 42.36; H, 2.05; N,
24.24%.
3.4.3. 2,4,6-Triamino-5-chloro-1,3-dicyanobenzene 7
Yield: 303 mg (76.0%), mp 327–328°C. IR: 3480, 3350, 3240, 2200, 1630, 1590, 1560, 1480, 1460,
1
1350, 1250, 790, 750 cm−1; H NMR (DMSO-d6): 6.11 (s, 2H), 6.28 (s, 4H); 13C NMR (DMSO-d6):
70.86, 89.20, 116.50, 150.53, 153.98. Anal. calcd for C8H6N5Cl (207.62): C, 46.27; H, 2.91; N, 33.73%.
Found: C, 46.33; H, 3.07; N, 33.47%.
1
3.5. H NMR experiments of chiral recognition
Solutions of 2–4 (0.05 mmol) and racemic compounds, 3,5-dinitrobenzoyl-10 -phenylethylamide,
benzoyl-10-phenylethylamide, N-3,5-dinitrobenzoylglycine isopropylester, Tröger’s base (0.05 mmol), in
CDCl3 (0.5 ml) were prepared in the NMR tube and the spectra run at ambient temperature. Comparison
with the NMR spectra in the absence of chiral selector revealed no separation of the enantiotopic protons.

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Acknowledgements
MM2 calculations were performed using ChemOffice Ultra 4.5, CambridgeSoft Corp., MA (USA),
Serial # 496311. The convergence criteria for the gradient of the potential energy surface (RMS gradient)
was set to 0.1.
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10. This assumption is confirmed by preliminary results with some chiral selectors that contain 1-naphthylethylamine (NEA)
bound to 1 in 4,6-positions. These structures still exhibit poor recognition, which is significantly enhanced, however, when
a proper spacer is incorporated between persubstituted aromatic ring and NEA unit.