Orchestrated catalytic double rollover annulation: Rapid access to N-enriched cationic and neutral PAHs

Article abstract of DOI:10.1039/c9cc02710f

Disclosed herein is a rhodium(iii)-catalyzed novel one-step back-To-back double rollover annulation on pyridine and pyrazine backbones leading to a structurally and optoelectronically diverse class of nicely decorated multi-ring-fused, extensively π-conjugated, N-enriched PAH molecules by virtue of orchestrated quadruple C-H activation events. Selected N-PAHs have been utilized as potential mitochondria and lysosome markers.

Full text of DOI:10.1039/c9cc02710f

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DOI: 10.1039/C9CC02710F
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Orchestrated catalytic double rollover annulation: Rapid access to
N-enriched cationic and neutral PAHs†
Pirudhan Karak,a Champak Dutta,a Tanoy Dutta,b Apurba Lal Koner*b and Joyanta Choudhury*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Disclosed herein is a rhodium(III)-catalyzed novel one-step back-
to-back double rollover annulation on pyridine and pyrazine
backbones leading to structurally and optoelectronically diverse
class of nicely decorated multi-ring-fused, extensively π-
conjugated, N-enriched PAH molecules by virtue of orchestrated
quadruple C–H activation events. Selected N-PAHs have been
utilized as potential mitochondria and lysosome markers.
Polycyclic aromatic hydrocarbons (PAHs) represent a privileged
class of molecules, immensely important in organic
electronics.1 Interestingly, PAHs decorated with heteroatoms
such as boron (B), nitrogen (N), and sulfur (S) exhibit
modulated optoelectronic properties due to modified
molecular energy levels and intermolecular interactions.1,2
Especially, the N-containing PAHs (N-PAHs) have drawn a
considerable recent attention by covering a wide range of
applications in diverse fields including materials science
(semiconductors, light emitting diodes, NLOs), and biology
(imaging agents).2 Therefore, appreciable efforts are being
devoted toward construction of tailored N-PAH architectures
with variable number, position and valence state of the
substituting N atoms thus allowing a systematic structure-
property understanding for judicious development of
application-apt molecules. Moreover, in parallel to neutral N-
PAH molecules, cationic N-PAHs can display further tuneability
of optoelectronic and supramolecular properties due to the
partially delocalized charge within the π-conjugated ring
framework.2 To fulfil the increasing demand of rapid synthesis
of a variety of such neutral and cationic PAHs including N-
PAHs, annulative π-extension (APEX) of (hetero)aromatic
molecules via transition metal-catalyzed C–H activation
reactions has emerged as a powerful protocol (Fig. 1A).3 The
Fig. 1 A) General scheme for annulative π-extension (APEX) reactions; B) previous work
on annulative π-extension of aryl/heteroaryl-imidazolium motifs; C) working hypothesis
of the present double rollover annulation protocol.
aOrganometallics & Smart Materials Laboratory, Department of Chemistry,
Indian Institute of Science Education and Research (IISER) Bhopal,
Bhopal 462 066, India. E-mail: joyanta@iiserb.ac.in.
bDepartment of Chemistry, Indian Institute of Science Education and Research
(IISER) Bhopal,
Electronic Supplementary Information (ESI) available: CCDC 1044320
1044321 3v), 1914692 3ab), 1044322 ), 1044323 ). See
DOI: 10.1039/x0xx00000x
Bhopal 462 066, India. E-mail: akoner@iiserb.ac.in
features such as step-economy, high efficiency and selectivity,
operational convenience etc. bring large benefits to the APEX
†
(3s),
(
(
(
4
(5
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J. Name., 2013, 00, 1-3 | 1
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protocol compared to traditional multistep methods. In this environment of strong chelating coordination by free N and N-
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context, beyond double C–H activation, there has been a heterocyclic carbene (NHC) donors.6
DOI: 10.1039/C9CC02710F
special focus toward inventing one-pot multiple C–H Initially, an optimization study was conducted for the present
activation-annulation approach to fuse multiple π-conjugated Cp*RhIII-catalyzed double rollover annulation reaction by using
rings surrounding the parent (hetero)arene backbone via 2,6-bis(1-methylimidazolium) pyridine hexafluorophosphate
sequential and extremely selective π-extension steps, thereby
adding more value to this novel chemistry. However,
(
(
1a) as the parent pyridine compound and diphenylacetylene
2a) as the annulating partner to yield the pentacyclo-fused
realization of such challenging methodologies has been cationic N-PAH 3a (Table 1A, and ESI, Table S1). The resulting
extremely limited to only a few reports.4.
optimal conditions of employing [Cp*RhCl2]2 (3 mol%) as
To target N-PAHs, our group has been successfully exploring catalyst, NaOAc (5 equiv.) as base, and AgOTf (5 equiv.) as
Cp*RhIII-catalyzed
APEX on imidazolium-containing oxidant in 1,2-dichloroethane solvent at 120 °C for a reaction
arenes/heteroarenes via double C–H activation followed by time of 12 h afforded 3a in 93% yield. Other bases (KOAc,
annulation with alkyne partner (Fig. 1B).4b,5 In the course of NaHCO3, K2CO3), other oxidants (AgOAc, Cu(OAc)2, Cu(BF4)2),
crafting multiple ring-fused, extensively π-conjugated, N- or other catalysts ([Cp*Co(CO)I2]) were found to be inferior or
enriched PAH architectures, herein we report an orchestrated ineffective. Similarly, shorter reaction time or lower
‘double rollover’ quadruple C–H activation annulation strategy catalyst/oxidant loading resulted in lower yield of 3a. Absence
on pyridine and pyrazine backbones with doubly-substituted of catalyst, base or oxidant led to the failure of annulation. (for
imidazolium motifs (Fig. 1C). This double rollover strategy details, see ESI, Table S1).
overcomes the challenge of direct multiple C–H Applying the standardized conditions, a series of multiple ring-
functionalization, in the presence of potentially poisoning
Table 1 Examples of A) cationic and B) neutral N-PAHs synthesized via double rollover annulation strategy
2 | J. Name., 2012, 00, 1-3
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reacting various 2,6-imidazolum-substituted pyridines and
pyrazines with several internal alkynes (Table 1A).
Diarylalkynes and dialkylalkynes could be used for this
DOI: 10.1039/C9CC02710F
annulation.
Notably,
phenyl–aryl
and
phenyl–alkyl
3g
unsymmetrical alkynes provided the major regioisomers 3f
,
and 3h in higher yields, and other isomers in lower or
negligible yields which could not be separated and isolated.
Notably, the major isomers resulted from the insertion of the
alkyne into the Cpy-Rh bond via placing the more electron-rich
aryl rings at the β-position to the metal. Benzimidazolium-
substituted pyridines and pyrazines were also applied
successfully to furnish the desired seven ring-fused N-enriched
polycyclic cations (3m
access different annulation and structural pattern within the
products, 2,5-imidazolum-substituted pyrazines were
-3p) in good yields. Furthermore, to
employed which afforded the zigzag pentacyclo-fused PAHs 3q
and 3r in good yields. Interestingly, this protocol could also be
modified further to produce neutral analogues of the above
multiple ring-fused N-PAHs. In this case, [Cp*RhCl2]2 (3 mol%)
was used as catalyst in combination with Cu(OAc)2 (3 equiv.) as
base as well as oxidant in toluene to annulate the 2,6- and 2,5-
(benz)imidazole-substituted pyridines and pyrazines providing
the desired neutral N-PAHs with a variety of functional groups
on the backbone (3s-3af) in 44-84% yields (Table 1B).
To examine the hypothesis of the Cp*RhIII-catalyzed ‘double
rollover’ annulation, although all the highly reactive
intermediates could not be isolated, two key bimetallic
rhodacyclic intermediates
4 and 5 akin to the species C and D
as shown in Fig. 1 were possible to be isolated from a reaction
of compound 1a and [Cp*RhCl2]2 (1a:Rh = 1:2) in presence of
Fig. 2 A) Synthesis of intermediates 4 and 5; B) crystal structures of 4 and 5; C)
stoichiometric and catalytic control experiments with 4 and 5.
NaOAc, (Fig. 2A). Intermediate
4 consisted two different types
of Rh metal centers – one center featuring imidazolium C–H
activated CNHC–Rh along with pyridine N-coordinated Npy–Rh
bonding while the other center featuring imidazolium C–H
activated CNHC–Rh along with pyridine rollover C–H activated
Cpy–Rh bonding (Fig. 2B). Monometallic intermediate with only
either (CNHC–Rh–Npy) or (CNHC–Rh–Cpy) type of bonding
alkene moiety or selectively stabilizing the LUMO upon making
the polycyclic backbone more electron-deficient, as going from
3a to 3b and 3j respectively (Figure 3A). In effect, the
molecules exhibited variable and tuneable fluorescence
colours from blue to cyan to green to dark orange at a
wavelength region of 440 nm–575 nm (Figure 3B,C).
Finally, a cationic N-PAH 3j and a neutral N-PAH 3s were
applied in cellular imaging studies as specific mitochondria and
lysosome-targeted biomarkers.7 Thus 3j was found to localize
selectively in the mitochondria of BHK-21 cells (baby hamster
kidney cell line) as verified by colocalization experiments with
commercial MitoTracker Red showing excellent overlap with
Pearson’s correlation coefficient of 0.92±0.04 (Figure 3D,
a,b,c). Similar co-staining studies in CHO cells (Chinese hamster
ovary cells) with 3s and commercial LysoTracker Red indicated
selective labelling of lysosomes in the living cells with the
corresponding Pearson’s correlation coefficient of 0.94±0.02
(Figure 3E, a,b,c). Moreover, 3j and 3s exhibited low toxicity to
the cultured cells in the working concentration range of 1 to
100 μM, as evaluated by MTT assay (Figure 3D, d and 3E, d).
environment (species
after using a stoichiometry of 1a:Rh = 1:1. The double rollover
intermediate having (CNHC–Rh–Cpy) bonding mode at both the
metal centers was formed upon further reaction of with
NaOAc and AgOTf (Fig. 2A,B). The plausible involvement of the
intermediates and during the catalytic annulation reaction
A or B, Fig. 1) could not be isolated even
5
4
4
5
was confirmed separately by performing both catalytic as well
as stoichiometric reactions as shown in Fig. 2C. These key
findings suggested the hypothesized catalytic cycle (Fig. 1C).
Evaluation of the electronic property of these multi-ring-fused
π-extended molecules at the frontier molecular orbital (FMO)
level by DFT (density functional theo-retical) calculations
showed that the HOMO (highest occupied molecular orbital) is
located on the di-aryl/dialkyl alkene side of the motifs whereas
the LUMO (lowest unoccupied molecular orbital) is located
over the central polycyclic backbone (Figure 3A). This well-
defined FMO property allowed us to decrease the HOMO-
LUMO energy gap via either selectively destabilizing the
HOMO upon introducing electron-donating group at the diaryl
In conclusion, we have successfully demonstrated
a
challenging double rollover annulation protocol for step-
economic construction of structurally and optoelectronically
diverse class of multiple ring-fused, extensively π-conjugated,
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6, 11943; (e) J. Chen, K. Yang, X. Zhou
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Fig. 3 A) Frontier molecular orbital (FMO) diagram of 3a, 3b and 3j; B) fluorescence
spectra (2 µM in H2O) and C) images of selected N-PAHs (10 µM in H2O); live-cell
confocal microscopy images showing the subcellular localization of D) 3j in BHK-21 cells
stained with a) 5 µM 3j, b) 300 nM of MitoTracker Red, c) merge image of a) and b); d)
MTT assay of 3j showing cell viability (concentration range 0–100 µM), and E) of 3s in
CHO cells stained with a) 5 µM 3s, b) 300 nM of LysoTracker Red, c) merge image of a)
and b); d) MTT assay of 3s showing cell viability (concentration range 0–100 µM).
6
For annulative rollover C–H functionalization catalysis on
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N-enriched, cationic and neutral PAH molecules, via
orchestrated quadruple C–H activation events on strongly-
chelating pyridine and pyrazine frameworks enabled by
commonly used Cp*Rh(III) catalyst. Selected designer
molecules displayed potential as fluorescent bioimaging
probes with specificity toward mitochondria and lysosome.
Funding from SERB-DST (EMR/2016/003002 to J.C.), and IISER
Bhopal (INGRANT/CHM/2012017 to A.L.K., and doctoral
fellowships to P.K., C.D. and T.D.) is gratefully acknowledged.
We thank Dr. Debasish Ghorai for help in crystallography.
Notes and references
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC02710F
Table of Contents Entry
Disclosed herein is a rhodium(III)-catalyzed novel one-step back-to-back double rollover annulation on
pyridine and pyrazine backbones leading to structurally and optoelectronically diverse class of nicely
decorated multi-ring-fused, extensively π-conjugated, N-enriched PAH molecules by virtue of
orchestrated quadruple C–H activation events.