Concise, aromatization-based approach to an elaborate C2- symmetric pyrenophane

Article abstract of DOI:10.1039/c2cc33611a

A very short synthesis (5 steps), the crystal structure and resolution of an elaborate, inherently chiral [n](1,6)pyrenophane is reported. The synthesis hinges upon two very productive events: a multicomponent reaction and an unprecedented double-McMurry/valence isomerization/dehydrogenation step. Aromatization reactions are involved in the formation of all four of the rings of the pyrene system.

Full text of DOI:10.1039/c2cc33611a

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Aromaticity
web themed issue
Guest editors: Nazario Martín, Michael Haley and
Rik Tykwinski
All articles in this issue will be gathered together
online at
www.rsc.org/cc/aroma

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 7747–7749
www.rsc.org/chemcomm
COMMUNICATION
Concise, aromatization-based approach to an elaborate C2-symmetric
pyrenophanewz
Penchal Reddy Nandaluru,a Prateek Dongare,a Christina M. Kraml,b Robert A. Pascal Jr.,c
Louise N. Dawe,a David W. Thompsona and Graham J. Bodwell*a
Received 18th May 2012, Accepted 12th June 2012
DOI: 10.1039/c2cc33611a
A very short synthesis (5 steps), the crystal structure and
resolution of an elaborate, inherently chiral [n](1,6)pyrenophane
is reported. The synthesis hinges upon two very productive events:
a multicomponent reaction and an unprecedented double-McMurry/
valence isomerization/dehydrogenation step. Aromatization reactions
are involved in the formation of all four of the rings of the pyrene
system.
reaction, salicylaldehyde (3) reacted with dimethyl glutaconate
(4) and cyclopentanone (5) in the presence of pyrrolidine to
afford DBP 6 in 69% yield (Scheme 1). Within 6 can be seen the
elements of a 4-substituted isophthalate, which corresponds to the
type of starting material used for the synthesis of 2.3 Reduction of
6 with LiAlH4 afforded triol 7 (95%). The difference in acidity of
the different types of OH groups (benzylic and phenolic) enabled
two units of 7 to be tethered by way of a highly chemoselective
O-alkylation reaction with 1,6-dibromohexane, which afforded
tetraol 8 (78%). At this point, the synthesis deviated from the
standard route, which would have involved conversion of the four
alcohols to bromides, formation of a dithiacyclophane, conversion
of the dithiacyclophane into a cyclophanediene (e.g. 10) and a
valence isomerization/dehydrogenation (VID) reaction to afford
For the [n]cyclophanes, i.e. those composed of one aromatic system
and one bridge, pyrene is the largest aromatic system to have been
used frequently. All but one of the known [n]pyrenophanes are
[n](2,7)pyrenophanes (1),1 which have C2v symmetry and are thus
inherently achiral systems.2 The exception is [10](1,6)pyrenophane
(2),3 which is C2-symmetric and thus an inherently chiral
cyclophane.4
The synthesis of 2 was modeled on the general synthetic
approach to the [n](2,7)pyrenophanes (1),1 but proved to be
problematic.3 As a result, work aimed at the development
of an improved synthetic approach to [n](1,6)pyrenophanes
(as well as [n](2,7)pyrenophanes) was initiated. The initial
results of this work are presented herein.
Inspiration for a new synthetic approach came from a
recently reported multicomponent reaction (MCR) that affords
6H-dibenzo[b,d]pyran-6-ones (DBP).5 In one example of this
a Department of Chemistry, Memorial University, St. John’s,
NL, Canada A1B 3X7. E-mail: gbodwell@mun.ca;
Fax: +1 709 864 3702; Tel: +1 709 864 8406
b Lotus Separations LLC, Department of Chemistry,
Princeton University, Princeton, New Jersey 08544, USA
c Department of Chemistry, Tulane University, New Orleans,
Louisiana 70118, USA
w This article is part of the ChemComm ‘Aromaticity’ web themed
issue.
z Electronic supplementary information (ESI) available: Experimental
procedures; characterization data and copies of 1H and 13C NMR
spectra; details of the resolution; details of the absorption and emission
spectra; Beer’s law plot; supplementary crystallographic information for
11. CIF for 11. CCDC 880434. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc33611a
Scheme 1 Synthesis of (1,6)pyrenophane 11.
Chem. Commun., 2012, 48, 7747–7749 7747
c
This journal is The Royal Society of Chemistry 2012

the pyrenophane (7 steps overall). Instead, tetraol 8 was oxidized
with PCC/Celites to afford tetraaldehyde 9 (72%) and this
compound was subjected to McMurry reaction conditions6 with
the intention of forming cyclophanediene 10 (along with an isomeric
cyclophanediene) directly. However, the only compound isolated
from this reaction was [12](1,6)pyrenophane derivative 11 (12%).
system can be assessed using the torsion angles through its
middle (C6-C7-C26-C27-C28-C16-C17-C29). For 11, the five
angles range from 160.0 to 174.11 and the average deviation
from 1801 (the value for a planar pyrene system) is 10.81. This
compares to a range of 159.9 to 170.51 and an average
deviation from 1801 of 14.11 in 2.3 The bend in the pyrene
system of 11 (as indicated by the smallest angle formed by
C7-C8-C26 and C17-C18-C16) is 17.41, which is also smaller
than the corresponding value in 2 (27.31).3,11 Relatively long
intramolecular C(sp3)ꢀHꢁ ꢁ ꢁp interactions12 (3.30 A) between
protons attached to C37 and C38 and the apical rings of the
pyrene system are also observed.12 The unit cell (space
1
The (1,6) bridging motif in 11 was evident from its H NMR
spectrum, which contained an AB system (d 7.89 and 7.69 ppm,
J = 9.2 Hz) for the protons attached to the pyrene system and
high field signals for some of the bridge protons (2H multiplets
centered at d 0.36, 0.14, ꢀ0.39 and ꢀ0.51 ppm), which lie across
the face of the pyrene system. The (1,8) isomer of 11 would have
exhibited two singlets for the pyrenyl protons and would not
have been expected to exhibit aliphatic signals at such high field.3
Although the yield of 11 was low, the result is noteworthy
for several reasons. First, the reaction delivers the target
pyrenophane directly, thereby replacing a 7-step sequence with
a 2-step sequence. The reaction is also very productive, as it
leads to the formation of three new carbon–carbon bonds and two
new aromatic rings. A likely order of events is two successive
intramolecular McMurry reactions leading to metacyclophanediene
10 followed by a VID reaction. The observation of dehydro-
genation under reductive (McMurry) conditions is not without
precedent when it results in the formation of an aromatic
system.7 In the present case, the high aromatic stabilization
%
group P1, Fig. S3) consists of two enantiomeric molecules
in a face-to-face arrangement with a closest pꢁ ꢁ ꢁp contact of
3.47 A.13
The absorption spectrum for 11 (Fig. 2) exhibits significant
complexity in the low energy absorption band envelope with
bands lmax (e, Mꢀ1 cmꢀ1) at 392 (1.4 ꢂ 104), 373 (3.2 ꢂ 104),
365 (3.0 ꢂ 104), 355 (2.5 ꢂ 104), 295 (3.9 ꢂ 104) and 283
(2.5 ꢂ 104) nm.14 Based on the linearity of Beer’s law plots
(ESIz), there is no evidence for aggregation below 6.0 ꢂ 10ꢀ5 M.
The fluorescence quantum yield (F) for 11 is 0.40 and the
fluorescence lifetime (tf) is 1.7 ns. This compares to F = 0.64
and tf = 480 ns for pyrene.15 The absorption features at
392 nm and the barely resolved band at 362 nm are not
apparent in the emission profile (Fig. 2). As a result, the mirror
image symmetry between the absorption and emission spectra
expected for a 2-state system is absent. These observations
imply that the lowest energy absorption band envelope is
comprised of two overlapping transitions and their vibronic
components, one of which leads to emission and the other to
non-radiative decay. At this juncture, a cautious interpretation
is that there is an inversion of the energetics and the nature of
the absorbing and emitting states, consistent with observations
made in other pyrene-based derivatives.15,16 A detailed study of
the excited state dynamics of 11 is underway.
energy of pyrene (74.6 kcal molꢀ1 8
) provides ample driving
force for dehydrogenation. Assuming that the reaction indeed
proceeds through metacyclophanediene 10, this is a very rare
example of a McMurry reaction leading to a [2.2]metacyclo-
phane9 and the first example of the McMurry reaction being
used to form both bridges of a [2.2]metacyclophanediene. The
presence of a tether between the two isophthalaldehyde units
in 9 is presumably advantageous in this regard. Finally, it
is interesting to note that (1,6)pyrenophane 11 was formed to
the exclusion of its (1,8) isomer. This is in contrast to the
dithiacyclophane-derived [10](1,6)pyrenophane (2), which was
formed as the minor component of a 4 : 7 mixture with
[10](1,8)pyrenophane.3
Small samples (ca. 10 mg) of (+)-11 (499% ee by HPLC)
and (ꢀ)-11 (499% ee by HPLC) were obtained by preparative
chiral phase HPLC (Chiralpak OD-H column: 40% ethanol
(0.1% diethylamine)/CO2, 100 bar). The CD spectra (Fig. 3) of
Pyrenophane 11 is
a rather elaborate derivative of
[12](1,6)pyrenophane, which means that the pyrene system
would be expected to be less distorted from planarity than
that of [10](1,6)pyrenophane (2).3 Indeed, the solid-state
structure of 11 (Fig. 1 and ESIz)10 revealed a pyrene system
that is less twisted than the one in 2. The twist in the pyrene
Fig. 2 Normalized absorption (red) and emission spectra (blue)
for 11 in CHCl3 (1 atm N2) at 298 ꢃ 3 K. [11] = 1.32 mM and
lexc = 350 nm.
Fig. 1 Asymmetric unit of 11 with 50% probability ellipsoids show-
ing intramolecular C(sp3)–Hꢁ ꢁ ꢁp contacts.
c
7748 Chem. Commun., 2012, 48, 7747–7749
This journal is The Royal Society of Chemistry 2012

J. J. Fleming, G. P. Manning, M. R. Mannion, B. L. Merner,
T. Sheradsky, R. J. Vermeij and M. Rabinovitz, J. Am. Chem. Soc.,
2004, 126, 6765; G. J. Bodwell, J. N. Bridson, M. Cyranski, J. W. J.
´
Kennedy, T. M. Krygowski, M. R. Mannion and D. O. Miller,
J. Org. Chem., 2003, 68, 2089; R. Y. Lai, J. J. Fleming,
B. L. Merner, R. J. Vermeij, G. J. Bodwell and A. J. Bard,
J. Phys. Chem. A, 2004, 108, 376.
2 The C2v symmetry arises upon time averaging of two degenerate
bridge conformers.
3 Y. Yang, M. R. Mannion, L. N. Dawe, C. M. Kraml, R. A. Pascal
Jr. and G. J. Bodwell, J. Org. Chem., 2012, 77, 57.
4 The term ‘‘inherently chiral cyclophane’’ is used here to denote a
cyclophane that is chiral in its parent form (the bare bones
assembly of arene(s) and bridge(s)), and not by virtue of the
presence of substituents on an otherwise achiral cyclophane.
5 P. R. Nandaluru and G. J. Bodwell, Org. Lett., 2012, 14, 310.
6 D. Lenoir, Synthesis, 1977, 553.
7 T. D. Lash, S. A. Jones and G. M. Ferrence, J. Am. Chem. Soc.,
2010, 132, 12786.
8 J. Wu, M. A. Dobrowolski, M. K. Cyranski, B. L. Merner,
´
Fig. 3 CD spectra for (+)-11 (black line) and (ꢀ)-11 (red line).
G. J. Bodwell, Y. Mo and P. v. R. Schleyer, Mol. Phys., 2009,
107, 1177.
the two enantiomers are nearly perfect mirror images and
the specific rotations ([a]2D3 = +130 ꢃ 201 (c = 0.13, CHCl3)
and [a]2D3 ꢀ120 ꢃ 201 (c = 0.14, CHCl3)) agree well. The
low precision is due to the small quantities of the pure
enantiomers.
9 G. J. Bodwell and P. R. Nandaluru, Isr. J. Chem., 2012, 52, 105;
B. L. Merner, L. N. Dawe and G. J. Bodwell, Angew. Chem., Int.
Ed., 2009, 48, 5487; T. Yamato, S. Miyamoto, T. Saisyo,
T. Manabe and K. Okuyama, J. Chem. Res., 2003, 63.
10 Crystal data for 11: C40H36O2, M = 548.69, triclinic, a = 9.395(5)
A, b = 12.771(6) A, c = 13.799(7) A, a = 104.045(8)1, b =
107.143(4)1, g = 106.279(6)1, V = 1419.9(12) A3, T = 153(2) K,
In summary, (1,6)pyrenophane 11 was synthesized in 4.4%
overall yield by a route that both starts and ends with a highly
productive reaction. The initial multicomponent reaction not
only brought together most of the atoms required for the
pyrenophane 11, but also generated a new aromatic ring that
ultimately manifested itself as the two apical rings in the
pyrene system. The synthesis culminated in a very unusual
twofold intramolecular McMurry/VID reaction, which generated
the two central aromatic rings of the pyrene system. As such, all
four of the rings in the pyrene unit were created during the
synthesis. Looking forward, the multicomponent reaction holds
promise for the synthesis of related pyrenophanes through
variation of the ketone and salicylaldehyde components of the
MCR (Scheme 2). There is also potential to vary the length of
the bridge (and thus the degree of deformation of the pyrene
system) by varying the length of the dihalide used in the
O-alkylation reaction. Asymmetric syntheses of these inherently
chiral cyclophanes are also conceivable. Work aimed at exploiting
these opportunities is underway.
space group P1, Z = 2, m(Mo-Ka) = 0.077 mmꢀ1, 13837 reflec-
%
tions measured, 5859 independent reflections (Rint = 0.0590). The
final R1 values were 0.0884 (I 4 2s(I))and 0.1271 (all data). The
final wR(F2) values were 0.1702 (I 4 2s(I)) and 0.1924 (all data).
The goodness of fit on F2 was 1.150. CCDC 880434.
11 The evaluation of bend using this metric requires the torsion angle
for C8-C26-C18-C16 to be close to 1801. For 11, the angle is 175.11,
which is comparable to 174.51 in 2 (ref. 3).
12 The C–Hꢁ ꢁ ꢁcentroid angles are 157.61 and 159.81, which qualifies
these interactions as meaningful, according to: E. Arunan,
G. R. Desiraju, R. A. Klein, J. Sadlej, S. Scheiner, I. Alkorta,
D. C. Clary, R. H. Crabtree, J. J. Dannenberg, P. Hobza,
H. G. Kjaergaard, A. C. Legon, B. Mennucci and D. J. Nesbitt,
Pure Appl. Chem., 2011, 83, 1619. Slightly longer C(sp3)–Hꢁ ꢁ ꢁp
interactions (3.39–3.51 A) between protons on C36 and C39 and
the two central rings of the pyrene system are not meaningful
because the C–Hꢁ ꢁ ꢁcentroid angles are less than 1301
(128.1–128.51). For discussions of the C–Hꢁ ꢁ ꢁp hydrogen bond,
see: G. R. Desiraju, Angew. Chem., Int. Ed., 2011, 50, 52, and
references cited therein.
13 While this distance may evoke thoughts of nascent p stacking, it is
important to bear in mind that the pyrene systems are twisted and
bent away from one another. Thus, the 3.47 A distance applies
only to the closest contact and not the full pyrene surfaces.
14 The photophysical properties of pyrene and pyrenyl derivatives
have been extensively documented.15,16 Briefly, following the
discussion of Hynes15 and based on the extensive studies of
Thulstrup,16 the assignments of four transitions and their vibronic
components that dominate the UV-vis absorption spectrum are
outlined below. The lowest energy transition is assigned to a So -
1Lb transition which formally forbidden. The So - 1Lb picks up
intensity through vibronic coupling with the So - 1La state that is
2700 cmꢀ1 higher in energy. This is clearly reflected in the ratio of
the oscillator strengths (fosc) of the So - 1La and So - 1Lb
transitions respectively where fosc(1La)/fosc(1Lb) = 120, and gives
rise to the complex vibronic structure observed in the UV-vis
spectra for pyrene. The two major higher lying transitions are
assigned So - 1Bb (36200 cmꢀ1) and So - 1Ba (41000 cmꢀ1),
respectively.
Scheme 2 Points of diversity for future (1,6)pyrenophane syntheses.
Notes and references
1 G. J. Bodwell, J. N. Bridson, T. J. Houghton, J. W. J. Kennedy and
M. R. Mannion, Angew. Chem., Int. Ed. Engl., 1996, 35, 1320;
G. J. Bodwell, J. N. Bridson, T. J. Houghton, J. W. J. Kennedy and
M. R. Mannion, Chem.–Eur. J., 1999, 5, 1823; G. J. Bodwell,
J. J. Fleming, M. R. Mannion and D. O. Miller, J. Org. Chem.,
2000, 65, 5360; G. J. Bodwell, J. J. Fleming and D. O. Miller,
Tetrahedron, 2001, 57, 3577; I. Aprahamian, G. J. Bodwell,
15 T.-H. Tran-Thi, C. Prayer, P. Uznanski and J. T. Hynes, J. Phys.
Chem. A, 2002, 106, 2244.
16 E. W. Thulstrup, J. W. Downing and J. Michl, Chem. Phys., 1977,
23, 307.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7747–7749 7749