Racemization barriers of atropisomeric 3,3′-bipyrroles: An experimental study with theoretical verification

Article abstract of DOI:10.1039/c6ra07585a

The significant rotational energy barrier about the stereogenic carbon-carbon bond of axially chiral 3,3′-bipyrroles has been investigated by electronic circular dichroism (ECD) spectroscopy, time dependent HPLC analysis, and computational modeling. The results elucidate pathways and transition states involved in configurational inversion, thereby confirming that 3,3′-bipyrrole derivatives can exist in stable and isolable atropisomeric forms.

Full text of DOI:10.1039/c6ra07585a

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Journal Name
ARTICLE
Racemization barriers of atropisomeric 3,3′-bipyrroles: An
experimental study with theoretical verification
Sourav Chatterjee,a Glenn L. Butterfoss,b Madhumita Mandal,a Bishwajit Paul,c Sreya Gupta,a
Richard Bonneau,d and Parasuraman Jaisankara,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The significant rotational energy barrier about the stereogenic carbon carbon bond of axially chiral 3,3’-bipyrroles have
been investigated by the electronic circular dichroism (ECD) spectroscopy, time dependent HPLC analysis, and
computational modeling. The results elucidate pathways and transition states involved in configurational inversion,
thereby confirming that 3,3’-bipyrrole derivatives can exist in stable and isolable atropisomeric forms.
www.rsc.org/
characterization, and calculations of racemization energy
barrier for various atropisomers.8b,10 Although, the field has
made substantial progress for important applications including
biology11-15 and materials science16 (Scheme 1), the
advancement has been quite sluggish due to the frequently
lower than desired biaryl activation barrier of racemization.17
For example, to date, only two regiospecific isomeric systems
of 1,1´-17a-c,f and 2,2´-bipyrroles17d-g (Scheme 2a) have been
investigated.
Introduction
Atropisomers are stereoisomers that principally arise due to
the constrained rotation of single bonds flanked by a pair of
hindered planar groups; the stereogenicity of these molecules
originates from the concept of axial chirality. These optically
active molecules allow the stable and specific presentation of
functional groups in space and are widely employed in
applications such as medicinal chemistry,1,2 molecular
devices,3 electrochemical polymerization,4 spectrochemical
and photophysical investigations,5 asymmetric catalysis,6 and
organic dyes.7 The biological activities, toxicities and
pharmacokinetics of an individual atropisomer may fluctuate
in biological environment due to significant diastereomeric
interactions.8 Although there is immense interest in biaryl
atropisomers, one of the major problems associated with their
practical application is that their chiral stability is often poor
due to an insufficient atropisomerization energy barrier.9 Thus,
an important area of research is to investigate new kinds of
atropisomers having significantly higher atropisomerization
energy and deduce the process of determination of their
thermodynamic properties.
Cl
Cl
Me
HN
NH
OMe
O
MeO2C
HO
NMe
OH
CO2Me
Me
O
OH
HO
O
H
MeN
N
N
N
Cl
Cl
O
MeO
OMe
Prodigiosin12
Isochrysohermidin13
(interstrand DNA cross-linking
properties)
Marinopyrrole A11
(potent immunosuppressive
and anticancer activities)
(anti bacterial)
Me
Me
CH3
Me
Me
Me
Br
Br
H3CO
N
N
CH3
N
O
B
F2
Me
X
X
N
N
NH
F2B
N
Me
Me
CH3
NH
Me
Br
Br
X = -Br or -Cl
NH
Owing to the high demand and importance of chiral biaryl
scaffolds, numerous reports describe the synthesis,
Polyhalogenated15
2,2'-bipyrrole
Me
(-)- Marineosin A14
(cytotoxicity against
colon tumour cell lines)
BODIPY DYEmer7a-b, 16
(fluorophore, laser dye,
biological labelling)
(from sea bird eggs)
a.Laboratory of Catalysis and Chemical Biology, Department of Organic and
Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick
Road, Kolkata - 700 032, India.
Scheme 1. Some important bipyrroles.
b.Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu
Dhabi-129188, United Arab Emirates.
We previously developed an unique pathway to construct 3,3´-
bipyrroles with highly constrained ortho-substitutions and
were able to successfully separate two individually pure
atropisomers.18 However, to the best of our knowledge, a
systematic study of the activation barrier of racemizations of
3,3´-bipyrrole systems has yet to be reported, which could
c. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA - 02115,
United States.
d.Center for Genomics and Systems Biology, New York University, New York, United
States.
* Corresponding author (email: Jaisankar@iicb.res.in)
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra of 5,5´-dimethyl-2,2´-diphenyl-1H,1´H-[3,3´]bipyrrolyl-4,4´-dicarboxylic acid
diethyl ester (1), ECD spectral analysis, HPLC profiles at different time intervals,
detailed procedure for determination of physical parameters, computationally enable us to identify stable enantiomers that may prove useful
evaluated conformers of 1 and additional computational data are provided]. See
DOI: 10.1039/x0xx00000x
in biology and materials science. A critical problem is of course
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ARTICLE
Journal Name
the overall stability of individual atropisomers for extended provide enough steric bulk to restrict its free rotation.19 The
periods of time at room temperature.
thermodynamic properties, such as activation barrier of
racemization (ΔG≠rac), activation entropy (ΔS≠rac) and activation
enthalpy (ΔH≠rac) were determined by Electronic Circular
Dichroism (ECD) spectroscopy and time dependent High
a) Previous work:
2,2'-bipyrrole
2,2'-terpyrrole
1,1'-bipyrrole
20
H
N
Performance Liquid Chromatography (HPLC) analysis.10,
N
N
Moreover, ab initio quantum mechanics theoretical
calculations were performed on the same molecule to verify
the experimental analysis. Herein, we describe the detailed
procedure of analytical and theoretical investigation which
N
N
N
N
H
H
H
H
ref. 16d-g
= ~2.5 Kcal. mol-1
ref. 9d
= ~5.4 Kcal. mol-1
ref. 16a-c, f
= ~2.0 Kcal. mol-1
G
G
G
(B3LYP)
(B3LYP)
(HF/6-31G*)
reveals the high conformational stability of
temperatures.
Having two pure atropisomers of 1 in hand, the kinetics of
1 at ambient
b) Is enantiopure 3,3'-bipyrrole system conformationally stable?
3,3'-bipyrrole
R6
H
racemization was determined by ECD spectroscopy.19, 10a
R4
N
R5
R6
NH
R3
G
= (?)
= (?)
R2
R1
R2
R1
R3
R5
N
H
(1-3)
N
H
(1-3)
No theoretical and experimental
calculation of rotational energy
barrier is reported
R4
H
H
H
N
CH3
N
CH3
N
CH3
tBuO2C
H3C
MeOC
H3C
EtO2C
H3C
CO2tBu
COMe
CO2Et
N
N
H
N
H
H
2
3
1
Scheme 2. Calculation of racemization energy barrier of
various atropisomeric bipyrroles.
Thus, given the established biological applications of bipyrrole
building blocks, we decided to study the stability of
atropisomerically pure 3,3´-bipyrrole derivatives (Scheme 2b).
Here, we investigated the rotational energy barrier of 5,5´-
dimethyl-2,2´-diphenyl-1H,1´H-[3,3´]bipyrrolyl-4,4´dicarboxylic
acid diethyl ester (
[3,3'-bipyrrole]-4,4'-diyl)bis(ethan-1-one) (
5,5'-dimethyl-2,2'-diphenyl-1H,1'H-[3,3'-bipyrrole]-4,4'
dicarboxylate as representative examples of 3,3´-
bipyrrole system.18b Molecule
was considered as an
1
), 1,1'-(5,5'-dimethyl-2,2'-diphenyl-1H,1'H
2) and di-tert-butyl
Figure 1. (a) CD spectroscopy of (R)-
recorded at 293 to 353 K, (each 10 K raise of temperature
required approximately 30 sec.) (b) CD spectroscopy of (R)-
(2.20 mM in EtOH) recorded at 353 K up to 160 min, (c) Plot of
CD (mdeg) of (R)- as a function of time (min) for the
1 (2.20 mM in EtOH)
(
3
)
a
1
1
exemplar of 3,3’-bipyrrole for this experiment since it is fully
substituted (which restricts the free rotation around its chiral
axis). Furthermore, the ester groups mounted at 4 and 4’-
position allow further functionalization. Notably, bulky
1
determination of conformational stability of enantiopure 3,3´-
bipyrrole. (d) Chiral HPLC profiles for time dependent
substituents, such as phenyl rings at 2 and 2’-position of 1 also
racemization of
1
at 353 K.
Time
Molecule
1
0
10
20
40
60
80
100
120
0.89
1.74
2.75
1.48
4.37
140
0.40
0.78
1.87
0.70
3.34
160
0.03
0.06
0.75
n.r.[d]
1.13
170
n.r.[d]
n.r.[d]
n.r.[d]
n.r.[d]
0.49
(min)
CD
(mdeg)
50.56
>99.0
>99.0
>99.0
>99.0
32.86
64.34
[n.d.]c
81.09
79.98
20.79
40.70
53.25
56.89
62.04
8.75
4.52
8.85
2.64
5.17
9.01
6.51
17.94
1.47
ee (%)[a]
ee (%)[b]
ee (%)[b]
ee (%)[b]
17.13
26.57
20.54
32.91
2.88
13.80
10.33
23.49
3.75
2
3
2.42
15.37
Table 1. Change of enantiomeric excess (ee) of compounds
1
-
3
with variable time interval at 353 K. [a] Decrease of CD intensity in
[b]
the form of enantiomeric excess with variable time intervals.
[c]
determined by HPLC analysis with variable time intervals. n.d. = not determined n.r. = not required (since
racemized at 140 min and 160 min respectively).
Decrease of enantiomeric excess
[d]
1 and 2 were
2 | J. Name., 2012, 00, 1-3
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Mode of
Molecule
Physical Parameters
analysis
Activation Barrier
of Racemization
(∆G≠rac, kcal.mol-1)
25.84
Temp
(T, K)
Decay
Rate Constant
(krac, sec-1)
Eq. Constant
(K≠
Half life
(t1/2
Consant (t1)
)
)
eq
1
22.590 min
63.182 min
94.496 min
7.377 x 10-4
2.637 x 10-4
1.763 x 10-4
10.034 x 10-17
3.692 x 10-17
2.543 x 10-17
15.75 min
43.78 min
65.48 min
353
25.78
25.28
343
333
CD
5.379 x 10-4
5.195 x 10-7
7.316 x 10-17
8.314 x 10-20
21.47 min
15.44 days
26.06
26.19
HPLC
353
300
30.985 min
22.279 days
2
3
HPLC
HPLC
353
353
30.653 min
41.051 min
5.437 x 10-4
7.395 x 10-17
21.24 min
28.45 min
26.05
26.26
4.060 x 10-4
5.522 x 10-17
Table 2. Different kinetic and thermodynamic parameters of 1-3 as a function of temperature.
Enantiopure (R)-
dynamic ECD analysis; CD spectra were recorded at 293 to 353 parameters, such as activation enthalpy (ΔH≠rac) and activation
K at intervals of 10 K. As anticipated, gradual decrease of entropy (ΔS≠rac) of the isomerization of atropisomer
were
determined by employing the Eyring equation (Eqn 2)20 and
found to be 27.49 kcal.mol-1 and 4.924 cal.mol-1.K-1
1 (2.20 mM in EtOH) was subjected to understand the mode of racemization, other thermodynamical
1
enantiomeric excess (ee; calculated from CD intensity) was
observed with increase of temperature (figure 1a). However,
complete racemization did not take place even up to 353 K (ee respectively from the Eyring plot (figure 2).19
of enantiopure (R)-
envisioned that the pure (R)-
racemic mixture, if we prolong the incubation time at 353 K. As
anticipated, complete racemization of (R)- was achieved after
160 min (figure 1b, table 1a). At lower temperatures (at 343 K
and 333 K) the ee of (R)- was significantly decreased within
the same incubation time (160 min) and complete where
1
was dropped to 54.06 % at 353 K).19 We
could be transformed to its
ꢀG≠rac = −RTln( hkrac ) = −RTlnK≠eq
TkB
1
κ
krac
T
ꢀH≠
R
1
kB ꢀS≠
1
ln
= −
+ ln
+
T
h
R
1
h
=
Planck constant,
κ
(kappa)= transmission
racemization was not attained (figure 1c) (ee dropped to 9.41 coefficient, T = temperature and kB = Boltzmann constant.
% at 343 K and 11.74 % at 333 K).19 We found the optimized
condition for complete racemisation of
1 is 160 min incubation
at 353 K. Similarly, we also investigated the kinetics of race-
mization for compounds 2 and 3; found that they took 140 and
170 min respectively to completely racemized (table 1).19 The
time dependent decrease of ee at 353 K was further used to
determine kinetic and thermodynamic parameters of
(table 2).19
1-3
A plot of CD intensity (mdeg) vs time at 353 K confirms a first
order exponential decay (figure 1c) giving a first order rate
constant (krac) 7.377 x 10-4 sec-1 and equilibrium constant to
the transition state (K≠eq) = 10.034 x 10-17. The activation
barrier of racemization (ΔG≠rac) as calculated from krac via the
Eyring equation (Eqn 1),19, 10a, 20 is 25.84 kcal.mol-1 at 353 K.
Activation barrier of racemizations (ΔG≠rac), similarly obtained
at 343 K and 333 K are comparable to the value at 353 K (table Figure
2. Eyring plot for the racemization of 1.
2). A large ΔG≠ supports the stability of enantiopure
rac
atropisomers of
1 at room temperature. Finally, in order to
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