F. Teodorescu et al. / Tetrahedron: Asymmetry 26 (2015) 1043–1049
1047
shift (d) values are given in ppm from internal TMS, and the
coupling constants J are in Hz.
Analytical TLC was performed with silica gel F254 (Merck) on
aluminum strips (10 cm length). The elemental analysis was
performed with an ECS 4010 COSTECH instrument. For column
chromatography and preparative TLC, silica gel 60 (Merck) and
silica gel F254 plates 20 ꢂ 20 cm (Merck) were used. The elution
solvents used for chromatography were diethylether and petrol,
boiling range 40–67 °C.
The chiral HPLC analyses were performed on a Chiralpak IC
column (5
l
m, 150 ꢂ 4.6 mm, hexane/ethanol 50:50 eluents,
1 mL minꢀ1 flow rate) on a unit composed of Merck D-7000 system
manager, Merck-Lachrom L-7100 pump, Merck-Lachrom L-7200
autosampler, Merck-Lachrom L-7360 oven, Merck-Lachrom
L-7400 UV-detector and Jasco OR-1590 polarimeter. Retention
times Rt in minutes, retention factors ki = (Rti ꢀ Rt0)/Rt0 and
Figure 5. Experimental HPLC-ECD spectra of (ꢀ)-(aR,aR)-1 (blue) and (+)-(aS,aS)-1
(red) compared with the TDDFT computed ECD spectra (CAM-B3LYP/TZVP, olive)
for the solution conformer of (aR,aR)-1; vertical bars represent rotational strengths
calculated at the CAM-B3LYP/TZVP level.
enantioselectivity factor
a = k2/k1 are given. Rt0 was determined
by injection of tri-t-butyl benzene.
4.1.2. IR and VCD measurements
IR and VCD spectra were recorded on a Bruker PMA 50 acces-
sory coupled to a Vertex70 Fourier transform infrared spectrome-
verified the results obtained with VCD and indicated that the
absolute configuration of (ꢀ)-trans-1 is (aR,aR).
ter.
A photoelastic modulator (Hinds PEM 90) set at l/4
retardation was used to modulate the handedness of the circular
polarized light at 50 kHz. Demodulation was performed by a
lock-in amplifier (SR830 DSP). An optical low-pass filter
(<1800 cmꢀ1) before the photoelastic modulator was used to
enhance the signal/noise ratio. A transmission cell equipped with
3. Conclusion
This study is a continuation of our previously related VCD study
of pyridine-N-oxide compounds. A similar compound to ( )-2,6-di-
sec-butyl-4-methylpyridine-N-oxide was synthesized, in which the
sec-butyl moieties were replaced with tolyl groups and the methyl
groups were attached to the pyridine ring. Major molecule struc-
tural changes took place either in the type of chirality or in the
flexibility of the molecule. The newly resolved enantiomers
(ꢀ)- and (+)-trans-2,6-di-ortho-tolyl-3,4,5-trimethylpyridine-N-oxide
are biaxially chiral and are rigid molecules that imply a unique
conformer. The synthesis and the resolution steps of the enan-
tiomers were detailed. The unique conformer was confirmed by
DFT calculations and it was shown that the conformation of the
enantiomer is given by the two simultaneous intramolecular
hydrogen bonds that form between the hydrogen of the methyl
groups belonging to the tolyl moieties attached to the pyridine-
N-oxide ring and the nitroxide oxygen. The experimental VCD
and ECD studies combined with DFT and TD-DFT theoretical
calculations were performed at various levels of theories and
showed that (ꢀ)-trans-1 had an (aR,aR)-absolute configuration.
A comparison of the experimental VCD spectra of (ꢀ)- and
(+)-2,6-di-sec-butyl-4-methylpyridine-N-oxide and of (ꢀ)- and
(+)-trans-2,6-di-ortho-tolyl-3,4,5-trimethylpyridine-N-oxide in the
frequency range 1200–1300 cmꢀ1, revealed that both have a
(+,ꢀ,+)/(ꢀ,+,ꢀ) triplet and when the sec-butyl moieties are replaced
with tolyl moieties, the peaks shift toward higher frequencies and
have higher intensities. The existence of this triplet could in the
future ease the VCD spectra interpretation of the pyridine like
compounds. Some supplementary data will be acquired in the
future so as to increase the database and to establish if possible a
correlation between the peak signs and a particular characteristic
of the pyridine compounds such as to be able to extrapolate the
finding to the entire class of optically active pyridine derivatives.
CaF2 windows and a 500 lm spacer was used and the solid samples
were measured in CCl4 at a concentration of 0.06 molꢁLꢀ1. Baseline
and artifact corrected VCD spectrum of one enantiomer was
obtained by subtraction of the VCD spectrum of a sample of the
opposite enantiomer and division by two. For the two enantiopure
samples the interferogram was averaged over totally two hours in
time slices of 15 min at a resolution of 4 cmꢀ1. For the infrared
spectrum the cell with CCl4 served as reference. The spectra are
presented without smoothing and further data processing.
4.1.3. HPLC-ECD measurements
Chiral HPLC separation of the trans-1 enantiomer were per-
formed on a Jasco HPLC system with Chiralcel OD column (5 lm,
150 ꢂ 4.6 mm, hexane/propan-2-ol 80:20 eluents, 1 mL minꢀ1 flow
rate) and HPLC-ECD spectra were recorded in stopped-flow mode
on a JASCO J-810 electronic circular dichroism spectropolarimeter
equipped with a 10 mm HPLC flow cell. ECD ellipticity (U) values
were not corrected for concentration. For an HPLC-ECD spectrum,
three consecutive scans were recorded and averaged with 2 nm
bandwidth, 1 s response, and standard sensitivity. The HPLC-ECD
spectrum of the eluent recorded in the same way was used as
background. The concentration of the injected sample was set so
that the HT value did not exceed 500 V in the HT channel down
to 210 nm.
4.2. Synthesis of pyridine-1-oxide 1 and the separation of the
stereoisomers
In Scheme 1 is presented the perchlorate of 2,6-di-o-tolyl-3,4,5-
trimethylpyrylium salt 5. Anhydrous aluminum chloride (67.0 g,
0.5 mol) was added in portions to o-toluyl chloride (154.5 g,
1 mol) under stirring and with external cooling in an ice/water
bath. Next, 42 g (0.5 mol) of 3-methyl-2-pentene 3 (obtained by
dehydration of 3-methyl-3-pentanol with sulfuric acid and
containing 15% 2-ethyl-1-butene 4) was added dropwise, while
maintaining the inner temperature under 10 °C. After stirring for
2–2.5 h at this temperature, the mixture was left overnight at room
temperature, then heated for 1 h at 45–55 °C and poured still
4. Experimental
4.1. Instrumentation
4.1.1. Synthesis and enantiomeric resolution
The NMR spectra were recorded with Varian Gemini 300 BB
instrument, operating at 300 MHz for 1H NMR and at 75 MHz for
13C NMR, in CDCl3 solution at room temperature. The chemical