Thermal racemization of biaryl atropisomers

Article abstract of DOI:10.1016/j.tetasy.2017.09.006

Many biaryl compounds possess atropisomerism due to the steric hindrance of substituents at the ortho-position of the two aromatic moieties. Upon heating, atropisomers may have enough energy to surpass the rotational energy barrier and racemize. The thermal stability of five atropisomers was studied using chiral chromatography by following the change in enantiomeric excess ratio at different temperatures. The first order racemization reaction rate was obtained at a given temperature as the slope of the change in enantiomeric excess ratio versus time. For each atropisomer, the racemization rates at different temperatures led to the value of the rotational energy barrier for racemization, ΔG^?, and to the racemization half lifetime, t_1/2, indicating the atropisomer thermal stability. Binaphthol started to racemize significantly at temperature of 190 °C and above while binaphthyldiamine was much more stable showing little or very minor racemization up to 210 °C. A chloro-substituted phenylamino-naphthol was very sensitive to thermal racemization starting at a low 40 °C.

Full text of DOI:10.1016/j.tetasy.2017.09.006

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Thermal racemization of biaryl atropisomers
Darshan C. Patel , Ross M. Woods , Zachary S. Breitbach , Alain Berthod a,b, Daniel W. Armstrong a,
a
a
a
⇑
a
Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX 76019, USA
Institut des Sciences Analytiques, Université de Lyon 1, CNRS, 5 rue de la Doua, 69100 Villeurbanne, France
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Many biaryl compounds possess atropisomerism due to the steric hindrance of substituents at the ortho-
position of the two aromatic moieties. Upon heating, atropisomers may have enough energy to surpass
the rotational energy barrier and racemize. The thermal stability of five atropisomers was studied using
chiral chromatography by following the change in enantiomeric excess ratio at different temperatures.
The first order racemization reaction rate was obtained at a given temperature as the slope of the change
Received 6 June 2017
Revised 24 August 2017
Accepted 8 September 2017
Available online xxxx
in enantiomeric excess ratio versus time. For each atropisomer, the racemization rates at different tem-
à
peratures led to the value of the rotational energy barrier for racemization,
D
G , and to the racemization
half lifetime, t1/2, indicating the atropisomer thermal stability. Binaphthol started to racemize signifi-
cantly at temperature of 190 °C and above while binaphthyldiamine was much more stable showing little
or very minor racemization up to 210 °C. A chloro-substituted phenylamino-naphthol was very sensitive
to thermal racemization starting at a low 40 °C.
Ó 2017 Published by Elsevier Ltd.
1
. Introduction
steric hindrance could be overcome at physiological temperature.
Racemization of an active ingredient of
devastating effects.
a drug may have
0
6
1
,1 -Biaryl atropisomers have received considerable attention as
chiral building blocks for chemicals and chiral catalysts for asym-
metric syntheses. Many biaryl atropisomers have interesting bio-
The kinetics involved in the racemization of biaryl compounds
were studied as early as 1935, where it was referred to as ‘optical
1
7
logical activities which make them the starting material for a
number of active pharmaceutical ingredients.2 The inclusion of
the biaryl scaffold in 4.3% of all known drugs, in addition to its
prevalence in other areas, has given it a distinction of a privileged
stability’. Several studies correlated the biaryl structure with the
8
magnitude of the racemization barrier. However, many of these
studies were carried out with atropisomers racemizing between
8
0 and 100 °C in time scales ranging from seconds to one hour.
A
2
a,3
motif.
Several commercial biaryl so-called ‘pure’ enantiomers
thorough study on the rotational energy barriers of stable
ortho-substituted atropisomers of polychlorinated biphenyls had
to work at temperatures between 270 and 425 °C to obtain racem-
were found to contain traces or even significant amounts of
enantiomeric impurities that were detected by high performance
liquid chromatography working with modern efficient chiral
9
ization in an hour time scale. A more recent study estimated the
4
stationary phases.
racemization barriers of two binaphthyls by computation using
1
0
The two possible enantiomers of axially chiral biaryls result
from the hindered rotation of the sigma bond linking the aryl moi-
eties. If the steric barrier to rotation is at least moderate
density functional theory.
In early work, changes in the atropisomer ratios were fol-
lowed by polarimetry where the accuracy greatly depended on
the magnitude of the optical activity of the studied isomers
(
>22.2 kcal/mol), the two atropisomers may be separated at room
5
a,3,5b
8
temperature.
However,
at
elevated
temperatures,
and on the temperature. Herein the thermal racemization of
racemization can occur for these compounds. Racemization of a
chiral catalyst would be deleterious for asymmetric synthesis. An
active pharmaceutical ingredient may also contain the biaryl
skeleton with stable atropisomers at room temperature, but the
biaryl atropisomers is revisited using modern powerful chiral liq-
uid chromatography using chiral stationary phases to accurately
follow even the smallest changes in atropisomer composition.
The kinetics as well as the thermodynamics of the biaryl racem-
ization are investigated at length for five previously unstudied
atropisomers.
⇑
Corresponding author.
E-mail address: sec4dwa@uta.edu (D.W. Armstrong).
https://doi.org/10.1016/j.tetasy.2017.09.006
957-4166/Ó 2017 Published by Elsevier Ltd.
0
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2
D. C. Patel et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
0
2
. Background
binaphthalen-2-ol [(S)-NOBIN], (R)-(+)-1,1 -bi(2-naphthol) [(R)-
0
BINOL], and (S)-(ꢀ)-1,1 -bi(2-naphthol) [(S)-BINOL] were pur-
0
The Eyring equation (Eq. (1)) relates the racemization rate con-
chased from Sigma–Aldrich (St. Louis, MO). The 2 -amino-
ꢀ
1
0
0
0
0
stant, k, in s , at different temperatures with the numerical barrier
energy value,
3 ,4 ,5 trichlorophenyl-1,1 -naphthalen-2-ol (TriChlophbin) and
à
0
0
D
G , in Joules per mol:
2 -aminophenyl-1,1 -naphthalen-2-amine (Phenap) compounds
were prepared in racemic forms using methods previously
reported and their pure enantiomeric forms were isolated using
z
K k
h
b
ꢀDG
k ¼
T e RT
ð1Þ
11
preparative HPLC.
where K is a transmission coefficient (0.5, dimensionless), h is the
ꢀ
34
Planck’s constant (6.63 ꢁ 10
J.s), k
b
is the Boltzman constant
3.2. Instrumentation
ꢀ
23
(
1.38 ꢁ 10
J/K); T is the absolute temperature in K, and R is the
gas constant (8.314 J/mol.K). Thus, the racemization rate constant,
All liquid chromatographic analyses were performed on an Agi-
lent 1260 Infinity HPLC system equipped with a degasser, a quater-
nary pump, an auto-sampler, a column thermostat, and a diode
array detector. The instrument was controlled by a computer run-
ning the Agilent OpenLAB chromatography data system (ChemSta-
tion Edition Rev. C.01.04). All peak areas used to calculate
enantiomeric excess (%ee) were corrected from baseline back-
ground and obtained from the OpenLAB software.
k, allows to obtain the racemization half life, t1/2, as:
ln 2
k
t
1=2
¼
ð2Þ
Racemization is a first order process that can be followed by
chiral HPLC. By monitoring the enantiomeric composition of a
given biaryl compound, at a constant temperature, T, it is possible
to calculate the enantiomeric excess ratio, ee. Plotting the log of ee
versus time produces a straight line whose slope gives the com-
pound racemization rate constant, k.
The chiral chromatographic columns LARIHC CF6-P
(
25 ꢁ 0.46 cm) and LARIHC CF7-DMP (25 ꢁ 0.46 cm) were pro-
11d–f,11c,11a
vided by AZYP, LLC (Arlington, TX).
They were packed
Once the rate constant k is obtained for several temperatures,
with 5 lm fully porous particles bonded with alkyl derivatized
à
the activation barrier energy value,
enthalpy,
D
G , and its constituent
cyclofructan 6 (Larihc CF6-P) or 3,5-dimethylphenyl derivatized
cyclofructan 7 (Larihc CF7-DMP) chiral selector and were used
with 90/10 heptane/EtOH or 90/10/0.1 heptane/EtOH/butylamine
à
à
DH , and entropy, DS , can be determined by plotting
ln (k/T) versus 1/T by rearranging the Eyring equation (Eq. (1)) as:
1
1c,1c
z
z
mobile phases in the normal phase mode.
flow rate was 1 mL/min and the sample injection volumes were
L. The diode array detector allowed for triple UV detection at
The mobile phase
lnðk=TÞ ¼ lnðk
b
=hÞ ꢀ
. Experimental
.1. Reagents
HPLC grade heptane and ethanol were purchased from Fisher
D
H =RT þ
D
S =R
ð3Þ
5
l
3
3
232, 254, and 280 nm. Note: 232 nm is the isobestic point for
BINAM and NOBIN. The column thermostat temperature was set
at ambient temperature (ꢂ24 °C), unless otherwise noted.
3
.3. Racemization protocol
Scientific (Waltham, MA). 1,4-Dioxane, diphenyl ether, and etha-
nol were obtained from Sigma–Aldrich (St Louis, MO). Figure 1
presents the structures of the five biaryl compounds studied.
For each analyte, 2 mg of the selected pure enantiomer were
dissolved in 2 mL of diphenyl ether (m.w. 170.2 g/mol; b.p.
0
0
Reagents (R)-(+)-1,1 -binaphthyl-2,2 -diamine [(R)-BINAM], (S)-
2
58 °C) and sealed under argon in a 20-mL headspace vial fitted
0
0
0
(
1
ꢀ)-1,1 -binaphthyl-2,2 -diamine [(S)-BINAM], (R)-(+)-2 -amino-
with a rubber septa cap. The vial was clamped 2-cm deep and cen-
tered in an oil bath covered with aluminum foil containing approx-
imately 2 L of heavy-duty hydraulic oil which prevented
temperature fluctuations for the duration of the study. The temper-
ature of the sample inside the vial was monitored using a Mastech
thermocouple MS8222H (Pittsburgh, PA, US) by lowering the probe
inside the vial. Small mL sample aliquots were drawn periodically
with a syringe connected to a 22-gauge non-coring needle. The
mL aliquot was diluted 10 times in ethanol and directly injected
into the HPLC system to determine the enantiomeric excess. The
needle was cleaned and oven dried before taking the next sample.
0
0
0
,1 -binaphthalen-2-ol
[(R)-NOBIN],
(S)-(ꢀ)-2 -amino-1,1 -
5
'
4'
3
'
6
'
2'
7'
OH
OH
NH
OH
2
8
8
'
1'
NH2
1
7
6
NH
2
2
3
5
4
BINOL
NOBIN
BINAM
Cl
4
4
. Results and discussion
.1. BINAM racemization
Cl
Cl
The protocol used to establish the thermodynamic parameters
NH2
NH2
NH2
for BINAM racemization is extensively described as an example
0
OH
of the study similarly done for all five biaryls (Fig. 1). 1,1 -Binaph-
0
thyl-2,2 -diamine stereoisomers are stable up to 170 °C. Significant
thermal racemization was observed at 230 °C. Figure 2 shows the
changes in enantiomeric composition as seen by the chro-
matograms obtained at different times when a 1 mg/mL (R)-BINAM
solution in diphenyl ether was maintained at 220 °C in an oil bath
for times ranging from few hours to several days. Figure 3 shows
the corresponding (R) and (S) compositions derived from the
chromatographic peak areas obtained from chromatograms as
Phenap
TriChlophbin
0
Figure 1. The structures of biaryl atropisomers studied. BINOL is 1,1 -binaphthyl-
0 0 0 0 0
,2 -diol; NOBIN is 2 -amine-1,1 -binaphthyl-2-ol; BINAM is 1,1 -binaphthyl-2,2 -
2
0
0
diamine; Phenap is 2 -aminophenyl-1,1 -naphthalen-2-amine; and TriChlophbin is
0
0 0 0 0
-amino-3 ,4 ,5 trichlorophenyl-1,1 -naphthalen-2-ol.
2
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D. C. Patel et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Figure 4. A plot showing ln(ee) versus time to show racemization rates of BINOL as
it was heated at temperatures 230, 240, and 250 °C at 1 mg/mL concentration in
diphenyl ether. Values calculated using the chromatographic peak areas.
Figure 2. Evolution of the chromatograms of a 1-mg/mL of (R)-BINAM solution in
diphenyl ether maintained at 220 °C for the indicated times (116 h are 4 days and
0
.99. Three different experiments performed for a single tempera-
2
R R
0 hours). (S)-BINAM t = 13.52 min; (R)-BINAM t = (R)-BINAM = 15.82 min. Col-
umn: LARIHC CF6-P (25 ꢁ 0.46 cm), mobile phase: heptane/ethanol 90/10 v/v,
ture of 250 °C show the reproducibility of the method. As alluded
to earlier in background section, once the rate constant k is
obtained for different temperatures for a compound, a ln (k/T) ver-
sus 1/T relation can be plotted (Eq. (3)) to determine the activation
barrier energy value as well as the enthalpy and entropy of activa-
tion. One such plot for BINOL is shown in Figure 5.
1
2
mL/min flow rate, 5 mL injection of 9/1 ethanol diluted sample; UV detection at
54 nm.
illustrated by Figure 2. The calculated enantiomeric ratio, ee, is
simply (R ꢀ S)/(R + S). The equation of the [ln (ee) versus time]
straight line was:
4
.2. Thermodynamic and kinetic data for biaryl racemization
2
lnðeeÞ ¼ ꢀ0:00000228t ꢀ 0:00636 ðn ¼ 9; r ¼ 0:997Þ
ð4Þ
Table 1 shows the thermodynamic and kinetic data experimen-
The slope of the ln(ee) versus t line is the reaction rate:
tally obtained for BINAM and all the biaryl compounds. The racem-
ization process implies simultaneous crossing of the
phenyl/naphthyl or naphthyl/naphthyl groups on one side of the
isomer and of the OH/OH or OH/NH or NH /NH polar groups on
ꢀ
6 ꢀ1
k = 2.28 ꢁ 10
s
for BINAM at 230 °C. Eq. (2) gives the time for
a
5
0% racemization as 304,000 s or 5067 min or 84.4 h. Eq. (1) gives
a rotational barrier energy,
à
DG , value of 178 kJ/mol. Reproducing
2
2
2
the same experimental work at different temperatures produces
10
the other side, a process called syn. The crossing may also occur
à
à
the corresponding k values that give the
DH and DS thermody-
on the other symmetric way for binaphthyl, i.e. for BINOL, the
namic values for the BINAM racemization reaction (Eq. (3)). An
experiment was done starting with a 1 mg/mL S-BINAM solution
at 250 °C giving exactly the same rate constant and barrier energy
0
naphthyl 8,8 -H’s crossing the hydroxyl groups and for BINAM,
0
the naphthyl 8,8 -H’s crossing the amine groups, this pathway is
10
called anti. For the phenyl-naphthyl compounds, the anti path-
ꢀ
6 ꢀ1
values (8.4 ꢁ 10
obtained starting with the pure (R)-atropisomer at the same
50 °C temperature. Figure 4 shows the racemization rates for
BINOL at different temperatures. The ln(ee) versus heating time
s) data are linearly fitted with correlation values that exceed
s
and 178.4 kJ/mol, respectively) as those
way is not symmetric; the phenyl NH
naphthyl on one side while the 6 -H of the phenyl group just
2
group hinders the 8-H
0
2
approaches the hydroxyl (TriChlophbin) or amine group (Phenap)
à
of the naphthyl moiety. The
D
G
energy barrier for racemization
(
is a macroscopic experimental all-inclusive measure of the ease
of such crossings, but not allowing one to determine if there is a
preferred syn or anti pathway.
100%
80%
60%
40%
20%
S-Binam
R-Binam
t1/2
enantiomeric excess
0%
0
1000
2000
3000
4000
5000
6000
7000
Time (min)
Figure 3. Changes in BINAM isomer composition and enantiomeric excess ratio (%
ee) upon heating at 230 °C for days a 1 mg/mL (R)-BINAM solution in diphenyl
ether. Values calculated using the chromatographic peak areas.
Figure 5. The ‘Eyring plot’ showing the change ln (k/T) versus 1/T for BINOL heated
at temperatures 230, 240, and 250 °C at 1 mg/mL concentration in diphenyl ether.
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4
D. C. Patel et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 1
Thermodynamic and kinetics data for Figure 1 biaryl thermal racemization reaction
à
à
à
Analyte
D
G
D
H
D
S
Temp
°C
Rate constant
s
t
h
1/2
T
%
DS percentage
ꢀ
1
ꢀ1
ꢀ1 ꢀ1
ꢀ1
kJ.mol
kJ.mol
J.mol
K
BINOL
165.4 ± 0.3
171.0 ± 0.3
178.4 ± 0.4
125.3 ± 0.5
110.7 ± 0.7
169.5
2.2
190
1.07E-06
6.61E-06
3.54E-05
1.67E-04
6.53E-07
3.97E-06
2.10E-05
9.81E-05
2.60E-07
2.21E-06
8.40E-06
3.95E-05
7.85E-08
1.08E-06
1.12E-05
9.23E-05
1.25E-07
7.34E-07
1.53E-05
1.56E-04
180
29
5.4
1.15
295
48.5
9.2
2.0
740
85
23
4.9
2450
178
17
0.62
0.64
0.67
0.70
0.22
0.23
0.24
0.25
10.9
11.3
11.8
12.2
14.7
15.6
16.5
17.4
20.3
21.1
22.6
24.0
2
2
2
10
30
50
NOBIN
174.4
160.7
106.2
86.9
0.8
200
2
2
2
20
40
60
BINAM
ꢀ40.1
ꢀ55.3
ꢀ75.2
210
2
2
2
30
50
70
60
Phenap
80
1
1
00
20
25
2.1
TriChlophbin
1535
262
13
37
60
80
1.2
The accuracy and precision of the method was assessed by making triplicate experiments at one temperature for each atropisomer.
4
.2.1. Phenyl versus naphthyl
racemization of the phenyl-naphthyl atropisomers via
a
à
As expected, the
DG rotational energy barrier is significantly
unidirectional route (anti) may explain the significant entropic
à
à
higher for the binaphthyl compounds (BINOL, NOBIN and BINAM)
than for the phenyl naphthyl compounds (Phenap and TriChloph-
bin). As the structures of the two phenyl-naphthyl compounds
show, the phenyl ring will be able to cross the naphthyl ring much
more easily than the naphthyl-naphthyl crossing. Clearly the steric
interaction between the close 8H and 8 H atoms of the two naph-
thyl groups is more pronounced than the analogous steric interac-
tion between the 6 H atom of the phenyl group and the 8H of the
naphthyl group (Fig. 1). Our experimental BINOL
contribution to the measured
D
G
(negative
D
S
value) for
BINAM, Phenap and TriChlophbin.
4.2.2. Amine groups versus hydroxyl groups
Another important factor that affects racemization is the nature
0
0
0
of the 2- and 2 -substituents on the binaphthyl or 1,1 -naphthyl-
0
phenyl compounds. In all cases, the 2,2 -substituents are polar
0
groups, either amine or hydroxyl groups or combinations thereof
à
D
G
value
(Fig. 1). For the three binaphthyl compounds, it is assumed that
à
(
169.5 kJ/mol) is consistent with the only literature value being
the naphthyl-naphthyl syn crossing contribution to the
D
G energy
à
6
% higher than the 158 kJ/mol calculated BINOL value found in
value is the same, the DG differences being attributed to the other
1
0
the literature and in the range of the 100 kJ/mol of dinaphthyl
side i.e. crossing of the two polar groups in the syn pathway. In the
dicarboxylic acids studied in the literature.8 The obtained
c
anti pathway, the 2- and 2 -polar groups cross respectively at the
0
à
0
racemization
D
G
values of the binaphthyl compounds are 30 –
8 H and 8 H naphthyl atoms. In either syn or anti pathways, the
à
5
0% higher (40 –60 kJ/mol higher) than those of the phenyl-
BINAM
D
G
with the crossing of two amine groups, is 13 kJ/mol
à
à
naphthyl compounds (Table 1). It was shown that when the
rotational energy barrier of binaphthyl atropisomers becomes
low enough, i.e., 94 kJ/mol for the simple 1,1 -binaphthyl, that
racemization starts at room temperature with a t1/2 lower than
one hour.
The major thermodynamic difference between the naphthyl
and phenyl groups is seen in the entropic contribution
BINOL and NOBIN racemization reaction takes place with almost
an exclusively enthalpy driven process. At all of the tested temper-
atures, the entropy contribution to
BINOL and 0.3% for NOBIN (Table 1). The two possible routes for
racemization syn and anti are equally difficult. The two phenyl-
naphthyl compounds presented significantly larger negative
values. For Phenap, at 100 °C, the entropic term was 16.5% of the
D
almost one fourth of the
entropic contribution to
observed for all compounds studied by Cagle and Eyring. Both
D
G
higher than the BINOL
versus 165.4 kJ/mol, respectively, Table 1). The NOBIN
an amine and a hydroxyl group and 171 kJ/mol is exactly between
DG with its two hydroxyl groups (178.4
à
DG with
0
à
the NOBIN and BINAM
DG values. The structure of the two naph-
8
c
thyl-phenyl atropoisomers are too different to draw any firm con-
à
clusion on the results, but here also, the biamine Phenap
D
G was
à
à
D
S . The
15 kJ/mol higher than the TriChlophbin
hydroxyl group in the 2 and 2 position, respectively.
D
G with an amine and a
0
à
TriChlophbin shows the greater
D
S
variation, ꢀ75.2 J/mol/K
à
D
G
was lower than 0.7% for
(Table 1). The amine group of TriChlophbin is strongly modified
by the electronegative character of the three chlorine atoms
attached to the shared phenyl ring (Fig. 1). To illustrate the mag-
à
D
S
nitude of this effect, it should be noted that the anilinium pK
a
is
This may
2
group does not behave like the
1
2
4.6 when the 2,3,4-trichloroanilinium pK
explain why this modified NH
one in NOBIN (no entropic contribution with DS = 0.8 J/mol/K,
a
is 0.1.
à
à
G
total energy barrier. For TriChlophbin, the T
D
S
value was
à
à
D
D
G
energy (24% at 80 °C). A positive
à
à
G , i.e. a negative
D
S
value, was
Table 1). Here also, it can be reasonably speculated that the
‘acidic’ amine group of TriChlophbin cannot cross the facing
8
a
à
negative and positive
Harris. A negative
pathway syn or anti would require much more energy than the
D
S
S
values were reported by Hall and
hydroxyl group (syn pathway) requiring the anti route to racem-
8
b
à
à
D
value may indicate that one rotation
ize and inducing the measured significant
D
S contribution mak-
à
ing more than 20% of DG (Table 1). Alternatively, the ground
other. Due to obvious size differences, the crossing of the two
state could have different degrees of rotational freedom which
are lost in the transition state. Further studies, perhaps involving
biaryl structural analogs, will be beneficial to understand these
phenomena.
NH
2
groups of BINAM or Phenap in the syn pathway is likely
0
more difficult than the crossing of an amine group with the 8 H
0
or 6 H in the anti pathway (Fig. 1). The greater ease of
Please cite this article in press as: Patel, D. C.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.006

D. C. Patel et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
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Z. S.; Woods, R. M.; Lim, Y.; Wang, A., Jr.; F.W.F.Armstrong, D. W. J. Org. Chem.
5
. Conclusions
2
016, 81, 1295–1299.
Biaryl atropisomers racemize upon heating. The kinetics of the
2. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930;
(b) Ding, K.; Li, X.; Ji, B.; Guo, H.; Kitamura, M. Curr. Org. Syn. 2005, 2, 499–545;
racemization reaction follow the Eyring equation. The temperature
needed to observe significant racemization is very dependent on
(
c) Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774–793.
3
4
.
.
Christie, G. H.; Kenner, J. J. Chem. Soc. 1922, 121, 614–620.
0
the atropisomer structure. Bulky groups at the 2,2 -position with
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Bielejewska, A.; Duszczyk, K.; Kwaterczak, A.; Sybilska, D. J. Chromatogr. A 2002,
naphthyl rather than phenyl groups enhance atropisomer thermal
0
0
stability. The atropisomers of 1,1 -binaphthyl-2,2 -diol, BINOL,
were found to be stable up to 180 °C with a half time of racemiza-
0
0
tion, t1/2, at this temperature of 20 days. 1,1 -Binaphthyl-2,2 -dia-
9
77, 225–237; (f) Zhan, F.; Yu, G.; Yao, B.; Guo, X.; Liang, T.; Yu, M.; Zeng, Q.;
mine, BINAM, is more stable with a racemization t1/2 at 210 °C of
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à
3
1 days (2 years at 180 °C). The strong negative
D
S
values
obtained with the diamine atropisomers may indicate that some
molecular arrangement is needed to make the rotation possible
through a particular syn or anti pathway. Recently, a newly devel-
oped compound, TriChlophbin, was sought for its potential antibi-
otic activity in living organisms. We also found that the thermal
stability of the atropisomers of this phenyl-naphthyl compound
was much lower than that of the binaphthyl compounds: the
TriChlophbin racemization t1/2 at 37 °C was found to be 11 days,
dropping to a week at 40 °C. Such information must be known
since the biological effects of the unwanted atropisomer may be
deleterious at trace amounts.
0
5
.
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7
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Acknowledgements
D.W.A. thanks the Robert A. Welch foundation for generous
support [Y-0026]. A.B. thanks the French National Center for
Scientific Research, ISA-CNRS-UMR5280, for continuous support.
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Please cite this article in press as: Patel, D. C.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.006