Configurational and conformational NMR study of enantiopure 2,2-dimethyl-1-(1-naphthyl)propanol via its carbamate derivatives

Article abstract of DOI:10.1002/(SICI)1097-458X(199912)37:12<885::AID-MRC572>3.0.CO;2-6

2,2-Dimethyl-1-(1-naphthyl)propanol was synthesized and the corresponding enantiomers were isolated by chiral HPLC. These enantiomers gave diastereoisomeric carbamates by reaction with (S)-(-)-1-phenylethylisocyanate, which were studied by NMR. The comparison of NMR data and molecular mechanics calculations allowed us to determine the absolute configuration of corresponding alcohols. Finally, x-ray results were in agreement with the absolute configuration proposed from the NMR spectra. Copyright

Full text of DOI:10.1002/(SICI)1097-458X(199912)37:12<885::AID-MRC572>3.0.CO;2-6

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 37, 885–890 (1999)
Configurational and conformational NMR study
of enantiopure 2,2-dimethyl-1-(1-naphthyl)propanol
via its carbamate derivatives
1
1
1
1
2
Marta Pomares, Xavier Grabuleda, Carlos Jaime, Albert Virgili, ∗ Angel Alvarez-Larena and
Joan F. Piniella
´
´
2
1
Department de Qu ´ı mica, Universitat Aut o` noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Department de Geologia, Universitat Aut o` noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
2
Received 6 April 1999; revised 24 June 1999; accepted 25 June 1999
ABSTRACT: 2,2-Dimethyl-1-(1-naphthyl)propanol was synthesized and the corresponding enantiomers were isolated
by chiral HPLC. These enantiomers gave diastereoisomeric carbamates by reaction with (S)-(ꢀ)-1-phenylethyliso-
cyanate, which were studied by NMR. The comparison of NMR data and molecular mechanics calculations allowed
us to determine the absolute configuration of corresponding alcohols. Finally, x-ray results were in agreement with
the absolute configuration proposed from the NMR spectra. Copyright  1999 John Wiley & Sons, Ltd.
1
KEYWORDS: NMR; H NMR; chiral HPLC; carbamates; molecular mechanics (MM); x-ray
INTRODUCTION
EXPERIMENTAL
Synthesis
With the aim of discovering the behaviour of chiral
compounds with certain conformational rigidity as chiral
solvating agents and chiral inductors, we have prepared
2
,2-Dimethyl-1-(1-naphthyl)propanone (2). A solution (1.6 M)
of butyllithium in hexane (7.8 ml, 12.48 mmol) was slowly added
to a diethyl ether (80 ml) solution of 1-bromonaphthalene (1.34 ml,
1
some tert-butyl derivatives of aromatic alcohols and
2
12.48 mmol) kept under N with continuous stirring. The reaction was
completed after 3 h, the mixture was cooled to 201 K and pivaloyl
amines. Some anthracene derivatives have been studied
2
from a stereochemical point of view and we have also
chloride (0.6 ml, 4.87 mmol) was added dropwise. After 10 h, the
reaction was quenched and the organic layer was separated, dried and
concentrated. The solid residue was purified by column chromatography
on silica gel (hexane/dichloromethane 90/10 v/v) to give white needles
3
tried to determine how chiral association is produced.
In the present paper we describe the preparation of
2,2-dimethyl-1-(1-naphthyl)propanol, 3, the isolation of
ꢀ1
(
61% yield), m.p. 73–74 °C; IR (KBr) cm : 3052, 2970, 2926, 1681
(C O), 1477 and 720. 1H NMR .CDCl / (ppm): 1.30 (s, 9H), 7.33
the two enantiomers by direct chromatographic separation
on a chiral column and their structural study. Moreover,
the reaction of an enantiopure isocyanate with racemic
alcohol, 3, gives diastereoisomeric carbamates, which are
3
(
dd, 1H), 7.43 (t, 1H), 7.49 (m, 2H), 7.60 (m, 1H) and 7.83 (m, 2H).
1
3
C NMR .CDCl
3
/ (ppm): 27.5, 45.8, 122.5, 124.5, 125.7, 126.4, 126.9,
128.6, 129.2, 130.2, 133.9, 139.2 and 214.7. EM m/z (%): 212 (16), 155
(100), 127 (33) and 57 (5).
4
easily separated by HPLC chromatography, and then
easily hydrolysed to enantiopure alcohols. In our case,
the use of isocyanate was indicated to obtain suitable
solid compounds to study by means of x-ray diffraction
techniques, so that their relative configuration could be
2,2-Dimethyl-1-(1-naphthyl)propanol (3). A diethyl ether solu-
tion (15 ml) of 2,2-dimethyl-1-(1-naphthyl)propanone, 2 (313 mg,
1
.48 mmol), was slowly added to a diethyl ether (70 ml) solution of
LiAlH (78.6 mg, 2.08 mmol) kept under N with continuous stirring at
4
2
room temperature. After 3 h, reduction was completed. The reaction was
quenched and the organic layer was separated, dried and concentrated.
5
determined. The structural study of the carbamates was
The solid residue was purified by column chromatography on silica gel
carried out by DNMR (dynamic NMR) and molecular
mechanics (MM) calculations. The energies associated
with the rotation around the carbonyl carbon–nitrogen
bond were measured. The relative configuration of each
diastereoisomer was determined by comparing chemical
shifts in NMR spectra and the results of NOE experiments
with the geometry proposed by MM calculations. Finally,
the result of the absolute configuration given by the x-ray
study confirmed the previous results.
ꢀ1
(
hexane/dichloromethane 80/20 v/v) (97% yield). IR (film) cm : 3450,
1
2952, 2871, 1364 and 785. H NMR .CD
4
7
3
COD
.65 (d, 1H), 5.41 (d, 1H), 7.46 (m, 2H), 7.49 (t, 1H), 7.70 (dd, 1H),
.79 (d, 1H), 7.88 (dd, 1H) and 8.23 (d, 1H). 13C NMR .CD
COD /
3
3
/ (ppm): 0.88 (s, 9H),
3
(
ppm): 26.5, 36.9, 73.0, 124.9, 125.3 (2C), 125.6, 126.4, 127.6, 129.1,
131.2, 132.5 and 139.4. EM m/z (%): 214 (6), 157 (100), 129 (90) and
7 (10).
5
2
0
Once the enantiomers of 3 were isolated, (C)-(R)-3: .[˛] D C25ꢀ2;
D
20
D
c D 1ꢀ42, CH
2
Cl
2
/; (ꢀ)-(S)-3: .[˛] D ꢀ28ꢀ1; c D 1ꢀ35, CH
2 2
Cl /.
N-(1-phenylethyl)carbamates (4a and 4b). Enantiomer (R)-3
83.5 mg, 0.39 mmol) and (S)-(ꢀ)-1-phenylethylisocyanate 99% (165 µl,
.17 mmol) were mixed and heated to 80 °C while protected by
(
1
4
*
Correspondence to: A. Virgili, Department de Qu ´ı mica, Universitat
a drying tube for 72 h, according to the literature. The mixture
was then chromatographed with toluene/choromethane (2 : 1, v/v).
Recrystalization from chloromethane gave white needles (71% yield),
m.p. 116–117
m/z (%): 361 (2), 305 (5), 157 (100) and 77 (11). C24H27NO calculated:
2
Aut o` noma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Contract/grant sponsor: CIRIT-CICYT; Contract/grant number:
QFN93-4427.
ꢀ
1
°
C; IR(KBr) cm : 3290, 2971, 1690, 1520, 1240. EM
Contract/grant sponsor: DGICYT; Contract/grant number: PB92-0611.
Copyright  1999 John Wiley & Sons, Ltd.
CCC 0749–1581/99/120885–06 $17.50

886
M. POMARES ET AL.
C, 79.77%, H, 7.49%, N, 3.87%; found: C, 79.73%, H, 7.18%, N, 3.87%,
RESULTS AND DISCUSSION
Synthesis and resolution
R,S)-4 ([˛]2 D C14ꢀ3; c D 1ꢀ02, CH
0
(
3
Cl).
D
The same reaction was used to obtain (S,S) diastereoisomer from
2
0
(
S)-3; m.p. 158–159 °C; (S,S)-4: ([˛] = -26.5; c D 1ꢀ31, CH
3
Cl).
D
Racemic 2,2-dimethyl-1-(1-naphthyl)propanol, 3, was ob-
NMR experiments
tained by reducing 2,2-dimethyl-1-(1-naphthyl)propanone,
2
. The reaction of the lithium derivative of 1-bromonaph-
7
NMR experiments were conducted on Bruker ARX400
thalene with pivaloyl chloride, yielded the ketone 2, 61%
(Fig. 1). 2,2-Dimethyl-1-(1-naphthyl)propanone, 2, was
also studied by NMR in order to assign the H and
spectrometers with a 5 mm QNP probe using CD COCD3
3
1
13
and CDCI as solvents. The operating frequency was
C
3
1
400.16 MHz for H. All the steady-state NOE experiments
NMR signals.
were obtained on degassed samples with the DPFGENOE
sequence using a mixing time of 600 ms; two dummy
scans were used.
Racemic 2,2-dimethyl-1-(1-naphthyl)propanol, 3, was
efficiently obtained by LiAlH reduction of 2. The
enantiomers were isolated by direct chromatographic
1
6
4
NMR experiments at low temperature of 4a and 4b
were recorded using CD COCD and the temperatures
was controlled to 0ꢀ1 C using the Bruker variable temper-
resolution using a Whelk-O1 (3R,4R)-4-(3,5-dinitrobenz-
8
amido)-1,2,3,4-tetrahydrophenanthrene as chiral column.
3
3
1
°
Hexane/ PrOH (98/2) was used as the elution solvent
ꢀ
1
ature unit. All tubes were degassed and the rate constants
with a flow of 3 ml min . The first enantiomer eluted
was (C)-3 and the second was (ꢀ)-3. Their absolute
configuration is (R)-(C)-3 and (S)-(ꢀ)-3, as shown at
the end of the paper (Fig. 6). Once the enantiomers
were isolated, they gave diastereoisomeric carbamates by
1
7
were determined using a line shape simulation program.
ꢀ
1
The results were, for 4a [T.K/, k.s /, υ.Hz/], (240,
3
1
.33, 27.8), (270, 120.6, 16.54), (300, 200, 0) and (330,
000, 0); for 4b [T.K/, k.s /, υ.Hz/], (250, 2.0, 17.02),
ꢀ
1
9
(270, 80.5, 8.06), (290, 166.6, 0) and (320, 333.3, 0). In all
reaction with (S)-(ꢀ)-1-phenylethylisocyanate: (R,S)-4a
of the simulations a natural linewidth of 3.45 Hz was used.
and (R,S)-4b, derived from first and second alcohols,
respectively (Fig. 2).
X-ray structure determination for compound 4a
Structural studies of carbamate derivatives
Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited with the Cambridge
Crystallographic Data Centre. Details of the crystals,
collection and processing, and refinement are as follows.
The complete assignment of the spectra signals was
1
1
carried out using methods which include H– H-
correlated two-dimensional techniques (COSY) and
1
1
homonuclear Hf HgNOE measurements (Table 1).
1
Crystal data. Colourless crystals were grown by vapour
H NMR spectra of the carbamate derivatives show, at
diffusion of pentane in a CH Cl solution. A prismatic
room temperature, a slow rotation around the amide bond
(Fig. 2). At 240 K, the NMR spectra of each carbamate
show an equilibrium between two differently populated
rotamers (Z and E), which indicates a difference in their
relative stability (Fig. 3).
2
2
crystal was mounted, 0ꢀ43 ð 0ꢀ14 ð 0ꢀ14 mm. C H NO ,
2
4
27
2
M D 361ꢀ47, orthorhombic, space group P2 2 2 (no. 19),
1
1 1
˚
˚
˚
a D 8ꢀ971 (1) A, b D 14ꢀ676 (3) A, c D 32ꢀ576 (4) A
(
from least-squares refinement on diffractometer angles
for 25 automatically centred reflections, 9ꢀ9 < Â <
°
At higher temperature, all resonances are broad
due to an increasing rate of conformational exchange,
3
ꢀ3
°
˚
1
ꢁ
2ꢀ1 ), V D 4289 (1) A , Z D 8, D D 1ꢀ120 g cm ,
c
ꢀ
1
D 0ꢀ70 cm (Mo K˛).
Data collection and processing. Data were measured
on an Enraf-Nonius CAD4 diffractometer using graphite-
˚
monochromated Mo K˛ radiation (ꢂ D 0ꢀ71069 A) and
°
a ω–2Â scan, T D 293 K, data collection range 2 <
°
2
 < 50 .0 Ä h Ä 10, 0 Ä k Ä 17, 0 Ä l Ä 38/, 3765
unique reflections. No significant variation in intensity of
one standard reflection was observed.
Structure solution and refinement. The structure was
1
9
solved by direct methods (SHELXS-86) and refined
2
by full-matrix least-squares procedures on F for all
1
9
reflections (SHELXL-97). All non-hydrogen atoms were
refined anisotropically, and hydrogen atoms were placed
in calculated positions with isotropic temperature factors
1.5 (methyl hydrogens) or 1.2 (the rest) times the Ueq
values of corresponding atoms. R.F/ D 0ꢀ066 and
2
R .F / D 0ꢀ170 for reflections with I > 2ꢃ.I/.
Figure 1. Synthesis of 3.
w
Copyright  1999 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 37, 885–890 (1999)

ENANTIOPURE 2,2-DIMETHYL-1-(1-NAPHTHYL) PROPANOL
887
0
0
Figure 2. Diastereoisomeric carbamates, 4a-(9R,7 S) and 4b-(9S,7 S).
Table 1. 1H-NMR assignment of 4a and 4b at 240 K in CD
COCD
3
3
1
[
υ. H) (ppm)]
0
tBu
H-2 H-3 H-4 H-5 H-6 H-7 H-8 H-9 H-7
NH
CH3
4
4
4
a-Z 7.60 7.45 7.76 7.86 8.21 6.25 4.94 6.76 1.36 0.59
—
—
a-E 7.52 7.35 7.76 7.82 7.40 7.45 8.25 6.23 4.64 1.36 0.92
b-Z 6.07 6.88 7.62 7.77 7.44 7.39 8.18 6.23 4.86 6.76 1.36 0.85
b-E 7.52 7.52 7.82 7.87 7.46 7.48 8.26 6.27 4.56 7.19 1.27 0.88
—
4
3 3
Figure 3. Part of NMR spectrum of 4a and 4b at 240 K in CD COCD .
finally achieving coalescence. Rate constants (k) were
Determination of the absolute configuration: NMR
experiments and MM calculations
1
determined for each diastereoisomer by a complete H
1
0
DNMR line shape analysis (CLSA) performed on a
resonance temperature dependence of the singlet H-g.
Molecular mechanics calculations were performed on
a Silicon Graphics INDY computer with R4600PC
processor using Still’s MacroModel v. 5.0 molecular
6D

G
values of the process were calculated using the
Eyring equation (Table 2). These values are consistent
with calculated barriers for carbamate rotation described
1
2
Ł
modelling package. MM3 was the selected force
1
b,11
13
in the literature.
field to carry out a full conformational analysis for
Copyright  1999 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 37, 885–890 (1999)

888
M. POMARES ET AL.
each carbamate. All rotatable bonds were driven in
(MM) the distances (Table 3) between H , H and the
2 3
centre of the phenyl ring.
°
°
°
successive steps from C180 to ꢀ180 at 15 increments.
Each structure was minimized in all variables except
the one being driven. All obtained energy minima
were fully optimized using the Polak–Ribiere conjugate
The distance values between H-2 and H-3 towards the
phenyl ring are very similar for both conformations (Z
or E) in one of the diastereoisomers (R,S), while the
same distances differ greatly between conformations (Z
or E) for the (S,S) diastereoisomer. This is reflected in
the similarity of the H-2 chemical shift of both rotamers
in carbamate 4a [H-2 (Z: 7.60; E: 7.52)] and the same
for H-3 in 4a [H-3 (Z: 7.45; E: 7.35)]. However, the
distance values for H-2 and H-3 and the phenyl ring are
markedly different in relation to the other diastereoisomer
(S,S), which explains the large difference in chemical shift
of these protons in each rotamer [H-2 (Z: 6.07; E: 7.52)
and H-3 (Z: 6.88; E: 7.52)] of the carbamate 4b derived
from the (ꢀ)-3 alcohol.
1
4
gradient (PRCG) minimization algorithm, allowing
enough cycles to ensure the convergence. In these
calculations CHCl was used as solvent, as described in
3
1
5
the GB/SA solvation model. The calculations revealed
for each carbamate that the rotamer of lower energy had
E geometry for both diastereoisomers (Table 3). This
result qualitatively agrees with the experimental energy
°
differences .G / between the rotamers deduced from
integrated NMR spectra (Table 2).
Assuming that the difference of chemical shifts (H-2
and H-3) of each rotamer of 4a compared to 4b arises from
the proximity of the phenyl aromatic ring, we calculated
On the basis of these results, we can assume that the
absolute configuration of carbamate 4a derived from the
first eluted alcohol-(C) is R and, by consequence, the
absolute configuration of the second alcohol-(ꢀ) is S.
In addition, some NOE experiments were made at
240 K by the irradiation of H-9 and H-7 of both rotamers
of each diastereoisomer (Figs 4 and 5). A NOE effect
Table 2. Experimental energy values
6D

G°
G
ꢀ
1
Compound %Z–%E (kcal/mol) Tc (K) k (s ) (kcal/mol)
(
(
R,S)-4a
S,S)-4b
20–80
25–75
0.65
0.56
300
290
200
170
14.20
14.09
t
was observed (Table 4) on the CH3 group and Bu
0
Table 4. NOE effect observed when H-7 and H-9 of 4a
and 4b were irradiated and the distances proposed by
˚
Table 3. Energy values (kcal/mol) and distances (A)
between H-2 and H-3 to the phenyl ring for each
diastereoisomer
MM
0
d(H-7 -Bu)
d(H-9-CH3)
Ł
Ł
˚
˚
MM3
Energy
d(H2-Ph)
d(H3-Ph)
MM3
(A)
NOE
(A)
NOE
(
(
R,S)-Z (4a)
R,S)-E (4a)
ꢀ22.46
ꢀ24.56
ꢀ20.64
ꢀ23.13
6.9
6.2
6.0
9.2
8.8
8.0
7.2
(R,S)-Z (4a)
(R,S)-E (4a)
(S,S)-Z (4b)
(S,S)-E (4b)
3.0
6.2
2.6
6.2
C
ꢀ
C
ꢀ
5.5
4.4
5.7
5.9
ꢀ
C
ꢀ
ꢀ
(
(
S,S)-Z (4b)
S,S)-E (4b)
10.7
1
Figure 4. (a) H NMR spectra of 4a. (b) Irradiation of H-9 E. (c) Irradiation of H-9 Z.
Copyright  1999 John Wiley & Sons, Ltd. Magn. Reson. Chem. 37, 885–890 (1999)

ENANTIOPURE 2,2-DIMETHYL-1-(1-NAPHTHYL) PROPANOL
889
1
0
0
Figure 5. (a) H NMR spectra of 4b. (b) Irradiation of H-7 E. (c) Irradiation of H-7 Z.
group, respectively, which is in agreement with calculated
distances assuming 4a in the (R,S) configuration and 4b
in the (S,S) configuration.
Suitable monocrystals of 4a were obtained and
subjected to x-ray analysis. Structures showed an
(
R,S) configuration, which agreed with the configuration
proposed from the NMR spectra. In the solid state, only
the Z conformation was observed (Fig. 6).
In the asymmetric unit there are two molecules
which have similar geometries. These two molecules
are associated into discrete dimers by means of two
NHÐ Ð ÐO C hydrogen bonds (Fig. 7). The distances in
Figure 7. X-ray dimeric structure of 4a.
˚
A were: (NHÐ Ð ÐO, 2.206(4); NÐ Ð ÐO, 3.045(7); N–H,
0
2
.860(5); N-HÐ Ð ÐO, 164.9(4); NHÐ Ð ÐO, 2.056(4); NÐ Ð ÐO,
.915(7); N–H, 0.860(6); N–HÐ Ð ÐO, 176.9(3)).
Acknowledgement
We thank the Servei d’Espectroscopia NMR of UAB for allocation
of spectrometer time. Financial support was obtained through grant
nos, QFN93–4427 and PB92-0611 from CIRIT-CICYT and DGICYT,
respectively.
Figure 6. X-Ray structure of 4a carbamate with (R,S)
configuration.
Copyright  1999 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 37, 885–890 (1999)

890
M. POMARES ET AL.
1
1. M. Remko and S. Schneider, J. Molec. Struc. (Theochem) 180, 175
1988).
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Magn. Reson. Chem. 37, 885–890 (1999)