Synthesis and structure of 2-substituted pyrene-derived scaffolds

Article abstract of DOI:10.1016/j.tetlet.2017.10.058

Pyrenes bear a propensity to form fluorescent excimers, and thus this chromophore is often found in sensors and fluorescent probes. 2-Functionalized pyrenes are of particular interest, however the preparation of these scaffolds is not trivial, involving synthetic routes that require 4,5,9,10-tetrahydropyrene as a key intermediate. Herein, the development and optimization of routes for the synthesis of 2-functionalized pyrene-derived building blocks, with potential to be used as tags in the preparation of fluorescent probes, is described. Additionally, the crystal structures of ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate and 2-acetyl-4,5,9,10-tetrahydropyrene revealed distinct conformations of the saturated tetrahydropyrene rings.

Full text of DOI:10.1016/j.tetlet.2017.10.058

Accepted Manuscript
Synthesis and structure of 2-substituted pyrene-derived scaffolds
Lília I.L. Cabral, Marta S.C. Henriques, José A. Paixão, Maria L.S. Cristiano
PII:
S0040-4039(17)31347-3
https://doi.org/10.1016/j.tetlet.2017.10.058
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Reference:
Tetrahedron Letters
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17 October 2017
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Please cite this article as: Cabral, L.I.L., Henriques, M.S.C., Paixão, J.A., Cristiano, M.L.S., Synthesis and structure
of 2-substituted pyrene-derived scaffolds, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.10.058
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Synthesis and structure of 2-substituted pyrene-derived scaffolds
Lília I. L. Cabrala, Marta S. C. Henriquesb, José A. Paixãob, Maria L. S. Cristianoa,*
aCCMAR and Department of Chemistry and Pharmacy, FCT, University of Algarve, Campus de Gambelas, Faro 8005-039, Portugal
bCFisUC, Department of Physics, University of Coimbra, P-3004-516 Coimbra, Portugal
*Corresponding author: Tel.: +351289800900 e-mail: mcristi@ualg.pt
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pyrenes bear a propensity to form fluorescent excimers, and thus this chromophore is often found in
sensors and fluorescent probes. 2-Functionalized pyrenes are of particular interest, however the
preparation of these scaffolds is not trivial, involving synthetic routes that require 4,5,9,10-
tetrahydropyrene as a key intermediate. Herein, the development and optimization of routes for the
synthesis of 2-functionalized pyrene-derived building blocks, with potential to be used as tags in the
preparation of fluorescent probes, is described. Additionally, the crystal structures of ethyl 4,5,9,10-
tetrahydro-2-pyrene-5-oxopentanoate and 2-acetyl-4,5,9,10-tetrahydropyrene revealed distinct
conformations of the saturated tetrahydropyrene rings.
Available online
Keywords:
2-Functionalized pyrenes;
Tetrahydropyrene;
Ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate;
2-Acetyl-4,5,9,10-tetrahydropyrene.
2009 Elsevier Ltd. All rights reserved.
interest due their useful properties,14 alternative synthetic
strategies for their preparation have been developed. One such
1. Introduction
Pyrenes are polycyclic aromatic systems that can undergo
stacking by π-π interactions, with propensity to form
strategy requires an indirect pathway, involving 4,5,9,10-
tetrahydropyrene 2 as a crucial intermediate.15
a
fluorescent excimers in solution and the solid state,1 and with a
high carrier mobility.2 As such, the pyrene chromophore is often
applied in sensors3 or fluorescent probes. Pyrene-based probes
have attracted considerable attention in recent decades7 due to
excellent spectroscopic properties, such as unusually long
lifetimes of fluorescence vibronic band structure8 and emission
showing a strong dependence on solvent polarity (Ham effect).9
For example, pyrene-based tags have been linked to lipids,4
proteins or nucleic acids,5,6 in order to build probes tailored to
specific applications in biological studies.
It has been shown that variations in the substitution pattern of the
pyrene ring and/or in the chemical nature of substituents enables
control over the molecular architecture, and thus the molecular
packing. This is especially relevant for some applications, for
instance if pyrene-based semiconductors are envisaged.10 As
such, reliable synthetic methodologies for pyrene substitution are
important, and must keep pace with molecular design.
Scheme 1. Retrosynthetic approach towards 2-functionalized pyrenes.
Herein, we describe the preparation of 2-functionalized
pyrene scaffolds using 4,5,9,10-tetrahydropyrene
2 as an
intermediate (Scheme 1). Pyrenes functionalized at the 2-
position are interesting because they retain the long axis of
symmetry, displaying a unique range of photophysical
properties that differ from those of the 1-substituted
analogues. Our work resulted in the synthesis and
characterization of 2-functionalized pyrene derivatives
bearing functionalities that enable the easy tagging of bio-
molecules, for instance through an ester or amide linkage,
for application to the preparation of fluorescent probes for
biological studies. Additionally, the crystal structures of
ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate 11 and
However, the regioselective synthesis of certain pyrene
derivatives is not trivial. While direct electrophilic aromatic
substitution of the pyrene system occurs almost exclusively at the
electron-rich 1, 3, 6 and 8 positions11 (Scheme 1), direct
substitution at positions 2 and 7 is known to take place only after
prior tert-butylation at the 2-position. In this case, the
unfavorable steric interactions induced by the bulky tert-butyl
group hinder substitution at positions 1, 3, 6 and 8.12 It has
recently been demonstrated that the iridium-catalyzed borylation
of pyrene allows the direct synthesis of a wide variety of pyrene
derivatives substituted at the 2- or 2,7-positions.13 Since pyrene
derivatives functionalized at positions 2 and 7 are of particular

2
2-acetyl-4,5,9,10-tetrahydropyrene
discussed.
7
are disclosed and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Compound proved to be photolabile; exposure to visible
light for a week led to extensive photodegradation
(DDQ).
6
.
2. Results and Discussion
Synthesis of 4,5,9,10-tetrahydropyrene
butyl)pyrene 4
2
and 2-(tert-
Our route towards 2-functionalized pyrenes began with the
partial reduction of pyrene to 4,5,9,10-tetrahydropyrene
(Scheme 2) prior to electrophilic aromatic substitution at
position 2. 4,5,9,10-Tetrahydropyrene was obtained via the
1
2
2
Pd-catalysed hydrogenation of pyrene (H2, 10% Pd/C,
THF:MeOH (1:5), 10 Bar, 7 d, 90 ºC) using an adapted
literature procedure.11,12 In this reduction, a mixture of
THF:MeOH as the solvent proved to be better than the
previously used EtOAc.11 This reaction proved to be quite
sensitive to the amount of pyrene present in the reactor;
upon increasing the amount of pyrene, complete reduction to
4,5,9,10-tetrahydropyrene
2 could not be achieved, possibly
Scheme 3. Preparation of 2-substituted pyrenes from 4,5,9,10-
tetrahydropyrene 2. Reagents and conditions: i) 1-chloropropane (1.1 eq.),
AlCl3 (1.2 eq.), CS2, -10 ºC, 36 h; ii) AcCl (1.1 eq.), AlCl3 (1.2 eq.), CS2, -10
ºC, 2 d; iii) Br2 (6.73 eq.), NaOH (18 eq.), 1,4-dioxane, H2O, 16 h; iv) DDQ
(2.1 eq.), THF, reflux, 2 d.
due to the excess substrate poisoning the catalyst surface.
Additionally, commercially available pyrene had to be
purified by column chromatography and carefully
recrystallised prior to reduction, in order to avoid the
formation of a mixture of desired compound
hexahydropyrene . Upon adjusting the reaction conditions
(solvent and amount of compound introduced into the
2 and
3
Friedel-Crafts acylation of
catalyst, and carbon disulfide (CS2) as solvent, afforded
crystals of 2-acetyl-4,5,9,10-tetrahydropyrene whose
2 using acetyl chloride, AlCl3 as
reactor), it was possible to form the desired product
2 in
90% yield. The reduction of pyrene under Birch conditions14
with lithium as reducing agent, was also attempted, however
this was unsuccessful. Additionally, this approach would not
7
structure was determined by single-crystal X-ray diffraction.
Friedel-Crafts reactions (alkylation and acylation) are
known to be sensitive to the solvent used; while CS2 leads to
monoacylation, CH2Cl2 affords the deacylated products.13
The reaction conditions were carefully tuned and
gratifyingly selectivity could be achieved by using only a
slight excess of the alkylating or acylating reagent (1-
chloropropane or acetyl chloride) in cold CS2.
form 4,5,9,10-tetrahydropyrene
catalysed dehydrogenation would therefore be necessary.
2 directly, and Pd/C
The tert-butylation of pyrene is known to be directed to the
2-position;15 in our hands the preparation of 2-(tert
-
butyl)pyrene
4 was achieved in good yields via Friedel-
Crafts alkylation, thus demonstrating that the introduction of
bulky substituents can be achieved without prior reduction
(Scheme 2). This compound is relevant because in future
work we aim to determine the non-specific effects on
membrane enzymology by evaluating the activity and
stability of a reconstituted ionic pump based on bilayers of
The dehydrogenation of
7
was achieved using a modified
was converted by
literature procedure.14 Compound
7
haloform oxidation to the corresponding carboxylic acid
8,
8
using bromine in 1,4-dioxane and NaOH.16 Compound
was then aromatized with DDQ to afford the target pyrene
2-carboxylic acid 10 (Scheme 3).
phospholipid/mixed cholesterol liposomes. Compounds
and will be used in this study.
4
5
In order to obtain 2-substituted pyrenes with a longer
aliphatic chain, thus increasing the flexibility of the system,
pyrene derivative 12 was prepared from 4,5,9,10-
tetrahydropyrene. Friedel-Crafts acylation, using AlCl3 and
ethyl glutaryl chloride in CS2, smoothly afforded the
monosubstitution product in good yield. The crystal
structure of 11 was determined by single X-ray diffraction.
This compound proved to be a versatile intermediate for
expanding the library of 2-substituted pyrenes.
Dehydrogenation of 11 with DDQ yielded ethyl 2-pyrene-5-
oxopentanoate 12, which was then hydrolyzed to carboxylic
acid 13. Compound 14 was obtained from compound 11
through a Clemmensen-type reduction using Zn and HCl in
EtOH and subsequently oxidized with DDQ to give ethyl 2-
Scheme 2. Reduction of pyrene
pyrene
(1:5), 10 bar, 80 ºC, 7 d; ii) AlCl3 (1.2 eq.), tert-butyl chloride (1.1 eq.),
1
and the preparation of 2-tert-butyl
4
. Reagents and conditions: i) H2/Pd(C) (0.65 eq.), THF/MeOH
CS2, -10 ºC, 36 h.
pyrenepentanoate 15
.
Hydrolysis of 15 gave the
corresponding carboxylic acid 16 in excellent yields
(Scheme 4).
Preparation of 2-substituted pyrenes from 4,5,9,10-
tetrahydropyrene 2
With 4,5,9,10-tetrahydropyrene
with the preparation of 2-functionalized derivatives. Friedel-
Crafts alkylation of using 1-chloropropane and AlCl3 as a
catalyst afforded compound (Scheme 3), which was then
converted into 2-isopropyl pyrene upon aromatization with
2 in hand, we proceeded
2
5
6

Scheme 4. Preparation of 2-substituted pyrenes from ethyl 4,5,9,10-
tetrahydro-2-pyrene-5-oxopentanoate 11. Reagents and conditions: i) ethyl
glutaryl chloride (1.1 eq.), AlCl3 (1.2 eq.), CS2, -10 ºC, 2 d; ii) DDQ (2.1 eq.),
THF, reflux, 2 d; iii) KOH (3.44 eq.), MeOH, H2O, 50 ºC, 1 d; iv) Zn (23
eq.), EtOH, HCl (37%), 3 d.
Ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate 11
Molecular geometry of 2-acetyl-4,5,9,10-tetrahydropyrene 7
and ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate 11
Figure 1. ORTEPII plot of compounds 7 and 11 showing the anisotropic
displacement ellipsoids drawn at the 50% probability level and the atomic
and ring numbering schemes.
The molecules of 2-acetyl-4,5,9,10-tetrahydropyrene
7 exist
in the crystal in two alternate conformations, A and B (see
Fig. 1), each having a probability close to 50% of sharing
the crystallographic sites. The saturated rings possess half-
chair conformations. In monomeric compound
7 the dihedral
3. Conclusion
angle between the least-squares planes of the two aromatic
rings is only 2.55(11)˚. The acetyl group is almost coplanar
with the aromatic ring, as shown by the small value of the
C1-C2-C17-O1 torsion angle of -1.0(2)˚. The oxygen atom
of the acetyl group acts as an acceptor of the methyl group
proton of a neighbouring molecule, this being the most
relevant intramolecular interaction contributing to crystal
cohesion in addition to those of Cg…Cg types.
Easy access to 2-functionalized pyrenes is relevant because
these scaffolds retain the long axis of symmetry, displaying
a unique range of photophysical properties that differ from
those of the 1-substituted analogues. Synthetic routes for the
conversion of pyrene into 2-functionalized pyrenes, using
4,5,9,10-tetrahydropyrene
2 as an intermediate, resulted in
the synthesis and characterization of various 2-
functionalized pyrene derivatives bearing functional groups
that may enable easy tagging of bio-molecules, for instance
through an ester or amide linkage, for the preparation of
fluorescent probes for biological studies. The crystal
structures of two intermediate compounds, ethyl 4,5,9,10-
tetrahydro-2-pyrene-5-oxopentanoate 11 and 2-acetyl-4,5,9,10-
In the crystal phase of ethyl 4,5,9,10-tetrahydro-2-pyrene-5-
oxopentanoate 11, the tetrahydropyrene moiety has an
approximate C2 symmetry axis running through the C13—
C14 bond. The molecule is slightly twisted as the two
aromatic rings (labelled
1 and 3 in Fig. 1) form a dihedral
angle of 16.57(5)˚. The two other rings (2 and 4) have close
to a screw-boat conformation, with average puckering
amplitude and angles18 calculated along the reference C9-
C10 and C4-C5 bonds of Q=0.452(4) Å, θ=114.6(3)˚ and φ=
209.0(5)˚. Bond lengths and angles within the molecule have
values close to the average tabulated values.
tetrahydropyrene 7, were also investigated, revealing distinct
conformations of the saturated tetrahydropyrene rings. It is
hoped that the information reported herein regarding the
synthesis and crystal data will help encourage the
incorporation of 2-pyrene derivatives into existing and novel
pyrene based applications and hopefully make their use as
popular as the substituted 1-substituted derivatives.
Additional crystallographic data for compounds
7 and 11
and a more in depth discussion of the crystal structures are
provided as supplementary information.
Acknowledgments
The authors gratefully acknowledge financial support from
Fundação para a Ciência e a Tecnologia (FCT), Portugal,
and
BIQ/112943/2009,
UID/Multi/04326/2013
FEDER,
through
projects
PTDC/MAR-BIO/4132/2014,
UID/FIS/04564/2016,
PTDC/QUI-
and
cofounded by QREN-COMPETE-UE. CCMAR and
CFisUC are also gratefully acknowledged.
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Supplementary Material
Experimental details for the synthesis and characterization
of compounds, single crystal X-ray structures,
crystallographic analysis, supramolecular organization of
ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate, 11 and
experimental details of the crystallographic studies, as well
as selected NMR and MALDI-TOF spectra, are included as
supporting information.

Synthesis and structure of 2-substituted
pyrene-derived scaffolds useful as
fluorescent tags
Lília I. L. Cabrala, Marta S. C. Henriquesb, José A. Paixãob,
Maria L. S. Cristianoa,*
aCCMAR and Department of Chemistry and Pharmacy, FCT, University of Algarve,
Campus de Gambelas, Faro 8005-039, Portugal
bCFisUC, Department of Physics, University of Coimbra, P-3004-516
Coimbra, Portugal
*Corresponding author: Tel.: +351289800900 E-mail: mcristi@ualg.pt
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x
Highlights
•
•
•
•
•
We report the optimised synthesis of key 2-functionalized pyrene
building blocks.
The compounds may be used as tags in the preparation of
fluorescent probes.
Crystal structures of tetrahydropyrene and 2-acetyl-
tetrahydropyrene are disclosed.
We report the crystal structure of ethyl tetrahydro-2-pyrene-5-
oxopentanoate (ETPO).
ETPO is a key block for access to ester- or amide-bridged
fluorescent probes.

6