Nonplanar aromatic compounds. 9. Synthesis, structure, and aromaticity of 1:2,13:14-dibenzo[2]paracyclo[2](2,7)-pyrenophane-1,13-diene

Article abstract of DOI:10.1021/ol702703b

(Chemical Equation Presented) Pyrenophane (6) and an octaphenyl derivative (16) were synthesized using two different routes. Both cyclophanes contain a severely bent pyrene unit (6: θ= 93.6° and 16: θ = 95.8°, according to DFT-calculations (B3LYP/6-311G**

Full text of DOI:10.1021/ol702703b

ORGANIC
LETTERS
2008
Vol. 10, No. 2
273-276
Nonplanar Aromatic Compounds. 9.
Synthesis, Structure, and Aromaticity of
1:2,13:14-Dibenzo[2]paracyclo[2](2,7)-
pyrenophane-1,13-diene
Baozhong Zhang,† Gregory P. Manning,† Michał A. Dobrowolski,‡
Michał K. Cyran´ski,‡ and Graham J. Bodwell*,†
Department of Chemistry, Memorial UniVersity, St. John’s,
Newfoundland, Canada A1B 3X7, and Department of Chemistry,
UniVersity of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
gbodwell@mun.ca
Received November 7, 2007
ABSTRACT
Pyrenophane (6) and an octaphenyl derivative (16) were synthesized using two different routes. Both cyclophanes contain a severely bent
pyrene unit (6: θ ) 93.6 and 16: θ ) 95.8 , according to DFT-calculations (B3LYP/6-311G**)), which was generated at room temperature by
°
°
a valence isomerization/dehydrogenation (VID) reaction. HOMA and NICS indicate 92
pyrene systems compared to planar pyrene.
−98% retention of aromaticity of the highly distorted
Cyclophanes constitute a very broad class of compounds,
which overlaps with various other classes of compounds. For
example, cyclophanes consisting solely of arylene units, can
also be viewed as cyclic oligoarylenes. Larger representatives
of such systems, e.g., hexa-m-phenylene (1) and related
systems,1 are usually categorized as shape-persistent mac-
rocycles,2 whereas smaller systems, e.g., 23 and 3,4 usually
attract attention from the cyclophane perspective.5 Exactly
how such systems are perceived is, of course, entirely viewer-
dependent. Whatever the perspective, there has been no
previous report of an oligoarylene cyclophane that contains
an arylene unit as large as a 2,7-pyrenylene unit,6 let alone
a severely bent one. We report here two synthetic approaches
to such a system.
Our group has synthesized several (2,7)pyrenophanes by
exploiting a valence isomerization/dehydrogenation (VID)
reaction of tethered [2.2]metacyclophane-1,9-dienes.7 As
part of an effort to apply this methodology more broadly,
pyrenophane 6 was identified as an attractive target. This
was arrived at through a process of incremental struc-
tural modification, which commenced with the parent
[n](2,7)pyrenophanes 48 (x ) 1-4) and progressed through
[2]paracyclo[2](2,7)pyrenophane 59 and then to 6. Pyreno-
(2) Grave, C.; Schlu¨ter, A. D. Eur. J. Org. Chem. 2002, 3075.
(3) (a) Williams, R. V.; Edwards, W. D.; Mitchell, R. H.; Robinson, S.
G. J. Am. Chem. Soc. 2005, 127, 16207. (b) Mitchell, R. H.; Iyer, V.
S.; Mahadevan, R.; Venugopalan, S.; Zhou, P. J. Org. Chem. 1996, 61,
5116.
(4) (a) Reiser, O.; Ko¨nig, B.; Meerholz, K.; Heinze, J.; Wellauer, T.;
Gerson, F.; Frim, R.; Rabinovitz, M.; de Meijere, A. J. Am. Chem. Soc.
1993, 115, 3511. (b) de Meijere, A.; Heinze, J.; Meerholz, K.; Reiser, O.;
Ko¨nig, B. Angew. Chem., Int. Ed. Engl. 1990, 29, 1418. (c) Chan, C. W.;
Wong, H. N. C. J. Am. Chem. Soc. 1988, 110, 462. (d) Reiser, O.; Reichow,
S.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 1277. (e) Wong,
H. N. C.; Chan, C. W.; Mak, T. C. W. Acta Crystallogr. 1986, C42, 703.
(f) Chan, C. W.; Wong, H. N. C. J. Am. Chem. Soc. 1985, 107, 4790.
† Memorial University.
‡ University of Warsaw.
(1) For example, see: (a) Staab, H. A.; Binnig, F. Tetrahedron Lett. 1964,
319. (b) Fujioka, Y. Bull. Chem. Soc. Jpn. 1984, 57, 3494. (c) Hensel, V.;
Schlu¨ter, A. D. Eur. J. Org. Chem. 1999, 451. (d) Hensel, V.; Schlu¨ter, A.
D. Chem. Eur. J. 1999, 5, 421.
10.1021/ol702703b CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/19/2007

phanes 4 and 5, which have clearly identifiable aromatic and
aliphatic moieties, are quintessential cyclophanes. By com-
Scheme 1. Synthesis of 6
parison, pyrenophane 6,10 which has no sp3-hybridized atoms,
can also be viewed as a cyclic oligoarylene.11 Either way,
the system contains a highly distorted pyrene moiety. Before
embarking on synthetic work, the bend angle (θ)12 of the
pyrene system was calculated at the AM1 level of theory.
The calculated value of 100.6°, although quite high, was well
within what the VID methodology had been able to deliver
in other systems.13
A more important consequence of having only sp2-
hybridized atoms is that the general Sonogashira-based
synthetic strategy8 employed for the syntheses of 4 and 5 is
not applicable to 6. In view of the three biaryl bonds present
in 6, a new strategy based on the Suzuki-Miyaura reaction
was devised (Scheme 1).
The synthesis began with the Suzuki-Miyaura coupling
of 1-bromo-2-iodobenzene (7) with (3,5-dimethylphenyl)-
boronic acid (8) to afford biphenyl 9 (87%).14 Suzuki-
Miyaura coupling of 9 with 1,4-phenylenebis(boronic acid)
(10) resulted in the formation of several compounds, from
which quinquephenyl 11 was isolated in 24% yield. An
alternative approach to 11 involving Suzuki-Miyaura cou-
pling of 8 with 2,2′′-dibromoterphenyl or 2,2′′-diiodoterphe-
nyl gave inferior results. Reaction of 11 with NBS under
irradiation with visible light afforded a mixture of brominated
products, ca. 70% of which (1H NMR analysis) was
tetrabromide 12. Attempts to isolate 12 by crystallization and
chromatography failed, so the crude product was treated with
Na2S/Al2O3.15 Again, the majority of the crude mixture
appeared to be the desired compound (13), but attempted
separations failed. The product mixture was then carried
though to cyclophanediene 14 without purification of the
intermediates via bis(S-methylation) with Borch reagent,16
thia-Stevens rearrangement, another bis(S-methylation) and
Hofmann elimination. Cyclophanediene 14 was obtained, but
it was contaminated with ca. 10% of pyrenophane 6.
Treatment of the mixture with DDQ in benzene at room
temperature gave, after chromatography, pure 6 (3% over
seven steps). The most significant losses were suffered during
the Hofmann elimination and VID reaction. The overall yield
of 6 from 4 was 0.8% (nine steps).
(5) (a) Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.; Wiley-
VCH: Weinheim, 2004. (b) Hopf, H. Classics in Hydrocarbon Chemistry;
Wiley-VCH: Weinheim, Germany, 2000. (c) Bodwell, G. J. In Organic
Synthesis Highlights; Schmalz, H. G., Ed.; Wiley-VCH: New York, 2000;
Vol. IV, pp 289-300. (d) de Meijere, A.; Ko¨nig, B. Synlett 1997, 1221.
(e) Bodwell, G. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2085. (f) Kane,
V. V.; de Wolf, W. H.; Bickelhaupt, F. Tetrahedron 1994, 50, 4575. (g)
Top. Curr. Chem. 1994, 172. (h) Vo¨gtle, F. Cyclophane Chemistry; Wiley:
New York, 1993. (i) Diederich, F. Cyclophanes; Royal Society of
Chemistry: London, UK, 1991. (j) Top. Curr. Chem. 1983, 113, 115. (k)
Cyclophanes; Keehn, P. M., Rosenfeld, S. M., Eds.; Academic Press: New
York, 1983; Vols. 1 and 2.
(6) To date, the largest arylene units that have been incorporated in an
oligoarylene-type cyclophane are 1,6-naphthalenyl and 2,8-(1,9-phenan-
throlinyl). See (a) Schafer, L. L.; Tilley, T. D. J. Am. Chem. Soc. 2001,
123, 2683. (b) Velten, U.; Rehahn, M. Macromol. Chem. Phys. 1998, 199,
127.
(7) For the original applications of this methodology, see: (a) Bodwell,
G. J.; Bridson, J. N.; Houghton, T. J.; Kennedy, J. W. J.; Mannion, M. R.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1320. (b) Bodwell, G. J.; Bridson,
J. N.; Houghton, T. J.; Kennedy, J. W. J.; Mannion, M. R. Chem. Eur. J.
1999, 5, 1823.
(8) (a) Bodwell, G. J.; Fleming, J. J.; Mannion, M. R.; Miller, D. O. J.
Org. Chem. 2000, 65, 5360. (b) Aprahamian, I.; Bodwell, G. J.; Fleming,
J. J.; Manning, G. P.; Mannion, M. R.; Merner, B. L.; Sheradsky, T.;
Vermeij, R. J.; Rabinovitz, M. J. Am. Chem. Soc. 2004, 126, 6765.
(9) Bodwell, G. J.; Miller, D. O.; Vermeij, R. J. Org. Lett. 2001, 3, 2093.
(10) We prefer the name 1:2,13:14-dibenzo[2]paracyclo-[2](2,7)pyreno-
phane-1,13-diene.
Although there was much room for improvement in the
synthesis of 6, the prospect of working primarily with
compound mixtures made this unattractive. Attention was
therefore turned to an alternative synthesis leading to an
(11) The cyclic system is shape-persistent, but the size of the cycle (16
atoms) and the small cavity (4.0 Å between the centroid of the central
benzene ring and the centroid of the C(10b)-C(10c) bond of the pyrene
system) make categorizing it as a macrocycle questionable.
(12) Bodwell, G. J.; Fleming, J. J.; Miller, D. O. Tetrahedron 2001, 57,
3577.
(14) The product arising from Suzuki-Miyaura coupling of 8 and 10
was obtained in 13% yield.
(13) Pyrenophanes with an AM1-calculated bend angle (θ) greater than
this (up to 113.4°) had already been isolated. (a) Reference 7b. (b) Reference
8. (c) Reference 12.
(15) Bodwell, G. J.; Houghton, T. J.; Koury, H. E.; Yarlagadda, B. Synlett
1995, 751.
(16) Borch, R. F. J. Org. Chem. 1969, 34, 627.
274
Org. Lett., Vol. 10, No. 2, 2008

octaphenyl derivative, 16, which was inspired by de Meijere’s
[2.2]paracyclophane derivative 154b and Mu¨llen’s work on
polyphenylenes17 and nanographenes.18
Scheme 2. Synthesis of 16
The synthesis of 16 (Scheme 2) started with the construc-
tion of tetraesterdiyne 17 in five steps from 5-hydroxyiso-
phthalic acid according to our previously published proce-
dures.8 Heating 17 with tetraphenylcyclopentadienone (18)
in diphenyl ether at reflux (bp ) 260 °C) gave tetraester 19
in 65% yield. Reduction of 19 with LiAlH4 afforded tetraol
20 (100%), which was reacted with PBr3 to generate tetra-
bromide 21 (55%). Compounds 19-21 were obtained as
slowly equilibrating mixtures of cis and trans isomers.19
Reaction of 21 with Na2S/Al2O3 yielded dithiacyclophane
22 in 83% yield, which is the highest yield yet obtained for
a dithiacyclophane using this reagent. Bridge contraction to
give 23 (73%) and double bond formation to give 24 (19%)
was achieved as for 13f14. The 14-step synthesis of
pyrenophane 16 (1.6% overall yield) was then completed
upon VID reaction (73%) of 24, again under remarkably mild
conditions (room temperature). The poor yield of 24 is yet
another indication that there is a need for the development
of superior methodology for the conversion of dithiacyclo-
phanes into cyclophanedienes.
In the 1H NMR spectra of 6 and 16 (Figure 1) the chemical
shifts of the protons on the p-phenylene ring were observed
at δ 5.67 and 5.54, respectively, which are not significantly
different from the corresponding protons in 5 (δ 5.54). The
protons of the pyrene systems of 6 and 16 appeared at δ
7.72 (Ha) and 7.47 (Hb) , and δ 7.60 (Ha) and 7.44 (Hb). The
analogous protons of 5 resonate at δ 7.67 (Ha) and 7.40 (Hb).
The similarity of these chemical shifts suggests that neither
the “benzannulation” of 5 nor the addition of eight phenyl
groups to 6 results in significant changes in the structure of
the pyrene system.
A series of geometry optimization and frequency calculations
at B3LYP/6-311G** level of theory20 found a Cs-symmetric
Despite many attempts to grow crystals of 6 and 16, none
that were suitable for an X-ray crystal structure determination
were obtained. Their structures were therefore calculated.
(17) Grimsdale, A. C.; Mu¨llen, K. AdV. Polym. Sci. 2006, 199, 1.
(18) (a) Wu, J. S.; Pisula, W.; Mu¨llen, K. Chem. ReV. 2007, 107, 718.
(b) Watson, M. D.; Fechtenko¨tter, Mu¨llen, K. Chem. ReV. 2001, 101, 1267.
(19) The comformational behavior of these and related compounds will
be addressed in a future publication.
Figure 1. 1H NMR spectra of 6 and 16.
Org. Lett., Vol. 10, No. 2, 2008
275

minimum energy conformation for compound 6 in which
the p-phenylene ring is twisted by 74.4° relative to the
neighboring o-phenylene units. Degenerate Cs minima in-
terconvert via a C2V-symmetric transition-state structure (in
which the p- and o-phenylenes are orthogonal), which is
calculated to be only 0.07 kcal/mol higher in energy. This
implies that the central fragment librates easily. This is
supported by the calculated lowest vibrational frequency for
the Cs conformer, which corresponds to libration of the
p-phenylene fragment and has an intensity of 46.8 cm-1.
In 16, unlike in 6, the lowest-energy structure has C2
symmetry, which results from the minimization of a close
nonbonded interaction between the “para” H atoms of the
two phenyl groups that point toward one another (see Figure
2). This H‚‚‚H distance is 3.199 Å, which compares to
lowest-energy conformers of 6 and 16 is 93.6° and 95.8°,
respectively. By comparison, the crystallographically deter-
mined value for 5 is 89.7°.9
Despite the large distortion from planarity, the π-electron
delocalization is highly preserved. The geometry-based
HOMA index21 for the pyrene system in 6 and 16 is 0.714
and 0.719, respectively. For planar pyrene, HOMA is 0.742,
which implies a 96-97% retention of aromaticity in the
pyrene systems of 6 and 16. The magnetism-based nucleus
independent chemical shift, NICS22 (computed at GIAO/
B3LYP/6-311G**), leads to an almost identical conclusion.
NICS for the central rings of both 6 and 16 is -4.5 ppm,
which compares to -4.4 ppm for planar pyrene (98%
retention of aromaticity). For the apical rings, NICS is -11.1
(6) and -11.0 ppm (16), which compares to -11.9 ppm for
planar pyrene (92-93% retention).
In summary, two syntheses of the 1:2,13:14-dibenzo-[2]-
paracyclo[2](2,7)pyrenophane-1,13-diene system have been
developed. The addition of eight phenyl groups (i.e., 6 to
16) does not significantly influence the geometry or the
aromaticity of the severely bent pyrene moiety. However, it
does offer the potential to gain access to pyrenophane-
graphene hybrids via cyclodehydrogenation.
Acknowledgment. G.J.B. gratefully acknowledges the
Natural Sciences and Engineering Research Council (NSERC)
of Canada. The ICM computer center, Warsaw (Poland) is
acknowledged for computational facilities.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra (1H and 13C)
for all pure compounds, total energies and Cartesian coor-
dinates at B3LYP/6-311G** for the geometries of 6 and 16,
and the full citation for reference 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Lowest-energy geometries of 6 and 16.
distances of 2.651 Å and 2.698 Å in higher energy (up to
1.4 kcal/mol) geometries having C2V or Cs symmetry,
respectively. In the C2-symmetric conformation, the macro-
cyclic oligoarylene framework is somewhat twisted. The
twist of the p-phenylene ring with respect to the o-phenylene
fragments is 84.8°, whereas the two o-phenylene rings are
twisted with respect to each other by 10.4°. In turn, the
peripheral phenyl rings are twisted with respect to the
o-phenylene units by 67.6-78.9°.
OL702703B
(21) (a) Krygowski, T. M. J. Chem. Inf. Comput. Sci. 1993, 33, 70. (b)
Review: Krygowski, T. M.; Cyran´ski, M. K. Chem. ReV. 2001, 101, 1385.
(c) Harmonic oscillator model of aromaticity is defined as: HOMA ) 1 -
R/N ∑(Ropt - Ri)2, where N is the number of bonds taken into the summation;
R is an empirical constant fixed to give HOMA ) 0 for a model nonaromatic
system and HOMA ) 1 for a system with all bonds equal to an optimal
value Ropt, assumed to be realised for fully aromatic systems. Ri stands for
a running bond length.
(22) (a) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A; Jiao, H.; van
Eikema Hommes, N. J. R. J. Am. Chem. Soc. 1996, 118, 6317. (b) Review:
Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R.
Chem. ReV. 2005, 105, 3842. (c) NICS was originally defined as the negative
value of the absolute shielding computed at the geometric centre of a ring
system. Rings with negative NICS values qualify as aromatic, and the more
negative the value of NICS become, the more aromatic the rings are.
The degree of distortion from planarity of the pyrene
moieties of 6 and 16 is similar. The bend angle (θ)12 for the
(20) Frisch, M. J.; et al. Gaussian, Inc.: Wallingford CT, 2004. See
Supporting Information for full citation.
276
Org. Lett., Vol. 10, No. 2, 2008