Synthesis, crystal structure, and resolution of [10](1,6)pyrenophane: An inherently chiral [n]cyclophane

Article abstract of DOI:10.1021/jo201013q

A synthetic approach to a set of three inherently chiral [n]cyclophanes, [n](1,6)pyrenophanes (29a-c, n = 8-10) was investigated. Progress toward 29a was thwarted by the failure of the key dithiacyclophane-forming reaction. For the next higher homologue, the synthesis was completed, but the desired [9](1,6)pyrenophane (29b) could only be partially separated from an isomeric pyrenophane, [9](1,8)pyrenophane (28b), and an unidentified byproduct. Work aimed at the synthesis of the next higher homologue resulted in the isolation of a 7:4 mixture of [10](1,8)pyrenophane (28c) and [10](1,6)pyrenophane (29c), which could not be separated by column chromatography or crystallization. However, single-crystal X-ray structures of 28c and 29c were obtained after manual separation of two crystals with different morphologies from the same batch of crystals obtained from the 7:4 mixture of 28c and 29c. The pyrene system of 29c was found to have a gentle end-to-end bend as well as a significant longitudinal twist. Short intermolecular C(sp³)- H???π contacts (2.64 to 2.76 A) between H-atoms on the bridge and the centroids of three of the four six-membered rings of the pyrene system of a neighboring pyrenophane of like chirality give rise to the formation of single enantiomer columns. From a DNMR study of the mixture of 28c and 29c, the bridge in [10](1,8)pyrenophane (28c) was found to undergo a conformational flip from one side of the pyrene system to the other with ΔG = 14.9 ± 0.2 kcal/mol. A two-stage preparative HPLC protocol was subsequently developed for the separation of 28c and 29c (Chiralpak AD-H column) and then the enantiomers of 29c (Chiralcel OJ-H column). This enabled the measurement of their optical rotations and CD spectra.

Full text of DOI:10.1021/jo201013q

Article
pubs.acs.org/joc
Synthesis, Crystal Structure, and Resolution of [10](1,6)Pyrenophane:
An Inherently Chiral [n]Cyclophane
Yixi Yang,† Michael R. Mannion,† Louise N. Dawe,† Christina M. Kraml,‡ Robert A. Pascal, Jr.,§
and Graham J. Bodwell*,†
†Chemistry Department, Memorial University, St. John’s, NL, Canada A1B 3X7
‡Lotus Separations LLC, Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
§
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States
S
* Supporting Information
ABSTRACT: A synthetic approach to a set of three
inherently chiral [n]cyclophanes, [n](1,6)pyrenophanes
(29a−c, n = 8−10) was investigated. Progress toward 29a
was thwarted by the failure of the key dithiacyclophane-
forming reaction. For the next higher homologue, the synthesis
was completed, but the desired [9](1,6)pyrenophane (29b)
could only be partially separated from an isomeric
pyrenophane, [9](1,8)pyrenophane (28b), and an unidentified
byproduct. Work aimed at the synthesis of the next higher
homologue resulted in the isolation of a 7:4 mixture of
[10](1,8)pyrenophane (28c) and [10](1,6)pyrenophane (29c), which could not be separated by column chromatography or
crystallization. However, single-crystal X-ray structures of 28c and 29c were obtained after manual separation of two crystals with
different morphologies from the same batch of crystals obtained from the 7:4 mixture of 28c and 29c. The pyrene system of 29c
was found to have a gentle end-to-end bend as well as a significant longitudinal twist. Short intermolecular C(sp3)−H···π
contacts (2.64 to 2.76 Å) between H-atoms on the bridge and the centroids of three of the four six-membered rings of the pyrene
system of a neighboring pyrenophane of like chirality give rise to the formation of single enantiomer columns. From a DNMR
study of the mixture of 28c and 29c, the bridge in [10](1,8)pyrenophane (28c) was found to undergo a conformational flip from
one side of the pyrene system to the other with ΔG⧧ = 14.9 0.2 kcal/mol. A two-stage preparative HPLC protocol was
subsequently developed for the separation of 28c and 29c (Chiralpak AD-H column) and then the enantiomers of 29c (Chiralcel
OJ-H column). This enabled the measurement of their optical rotations and CD spectra.
considerable number of inherently chiral parent cyclophanes
are known, a small selection of which (4,3 5,4 6,5 and 76) is
shown below. Only a few inherently chiral parent cyclophanes
have been resolved, e.g., 5 and 7. Furthermore, virtually all of
the inherently chiral cyclophanes reported so far are composed
of more than one aromatic system.7 A series of [n](2,5)-
pyridinophanes (n = 8−12; compound 7 when n = 9) are the
only examples of inherently chiral [n]cyclophanes (i.e., those
composed of a single aromatic system and one bridge).6
Remarkably, the resolved enantiomers of pyridinophane 7 were
reported to be configurationally very stable, maintaining their
optical activity after prolonged heating at 250 °C! Only the
highest homologue of 7 (n = 12) was found to be
configurationally unstable at room temperature.
INTRODUCTION
■
Stereochemistry is one of the many interesting facets of
cyclophane chemistry,1 and a significant body of literature on
chiral cyclophanes exists.2 Parent cyclophanes, i.e., the bare-
bones assemblies of aromatic units and bridges, can be achiral
or chiral, but most of the quintessential cyclophane systems,
e.g., [2.2]paracyclophane (1), are of the achiral variety. These,
however, can become chiral when appropriately substituted,
either on the aromatic system, e.g., 2, or, less commonly, on the
bridge, e.g. 3 (Scheme 1). Indeed, a large majority of known
Scheme 1. Substitution of an Inherently Achiral Cyclophane
to Give Chiral Cyclophanes
The synthesis of inherently chiral and configurationally stable
parent [n]cyclophanes requires an aromatic system with
enantiotopic faces (including consideration of the bridging
motif) and this rules out benzene, regardless of the bridging
chiral cyclophanes are derivatives of inherently achiral cyclo-
Received: May 20, 2011
Published: November 27, 2011
phanes (especially [2.2]paracyclophane (1)).2 Nevertheless, a
© 2011 American Chemical Society
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motif. Larger benzenoid aromatic systems with particular
bridging motifs (e.g., [n](2,6)naphthalenophanes) and various
mononuclear heteroaromatic systems with particular bridging
motifs (e.g., [n](2,5)pyridinophanes) are therefore needed, as
are concise, general synthetic approaches. The bridge must also
be short enough to provide configurational stability. With these
issues in mind, it is interesting to note that there are relatively
few reports of [n]cyclophanes derived from aromatic systems
larger than benzene regardless of whether they are inherently
chiral or not.8
separated, this would allow the chiroptical and photophysical
properties of a chiral pyrene system (a much more interesting
chromophore than pyridine) to be studied.
RESULTS AND DISCUSSION
■
The key 1,2,4-trisubstituted building block, diethyl 4-
bromoisophthalate (18), was synthesized from 4-bromo-m-
xylene (16) using an oxidation/esterification sequence (43%,
two steps) (Scheme 3). At this point, an eight-carbon bridge
Scheme 3. Synthesis of Tetrabromides 22a−c
Pyrene is a promising aromatic system for incorporation into
a chiral and configurationally stable [n]cyclophane. There are
several bridging motifs that render the faces of this polynuclear
aromatic system enantiotopic, and it is large enough that
interconversion of the enantiomers by way of a “skipping rope”
process is likely to be difficult, even with reasonably long
bridges (cf. [9](2,5)pyridinophane (7)). Lastly, and perhaps
most importantly, a range of [n]pyrenophanes has been
reported over the past two decades using a common synthetic
approach.9 Although these systems have all been inherently
achiral (2,7)pyrenophanes (11), the general synthetic approach
should be easily adapted for the synthesis of inherently chiral
(C2-symmetric) [n](1,6)pyrenophanes (15) simply by chang-
ing the substitution pattern of the starting material from a 1,3,5-
trisubstituted benzene (8) to a 1,2,4-trisubstituted benzene
(12) (Scheme 2). Instead of just an end-to-end bend, which is
Scheme 2. Synthetic Approach to [n](2,7)Pyrenophanes
(11) and Proposed Approach to [n](1,6)Pyrenophanes (15)
(VID = Valence Isomerization/Dehydrogenation)
was chosen to link two aromatic building blocks because it was
expected to impart significant, but not excessive, twist to the
pyrene system in the target [8](1,6)pyrenophane. Accordingly,
Sonogashira reaction of 18 with 1,7-octadiyne (19a) afforded
diynetetraester 20a (69%). The alkyne functionalities were
removed by catalytic hydrogenation (96%), and the resulting
tetraester 21a was converted into tetrabromide 22a by
sequential reaction with LiAlH4 and PBr3 (79%, two steps).
The reaction of tetrabromide 22a with Na2S/Al2O3 was
expected to give a mixture of isomeric dithiacyclophanes 23a
and 24a (Scheme 4). Two isomers can form because the faces
of the two benzene rings are prochiral and can therefore be
connected in a face-to-face or face-to-back fashion. Obtaining a
mixture at this point was expected to be unavoidable, and
separation at this stage or later in the synthesis was a part of the
plan. However, treatment of tetrabromide 22a with Na2S/
Al2O3 gave little or none of the desired dithiacyclophanes 23a
1
and 24a. The H NMR spectrum of the crude product was
more complicated than expected for a mixture of 23a and 24a,
and the APCI(+) mass spectrum showed a base peak at m/z =
765. This corresponds to [M + 1]+ for tetrathiacyclophanes
resulting from the coupling of two molecules of tetrabromide
22a. The situation, however, is complicated as 16 isomeric
structures are possible. These can be broadly categorized
according to the way in which the CH2SCH2 bridges connect
the two sets of tethered arenes, i.e., 25−27 (Scheme 4).
present in the pyrene system of the [n](2,7)pyrenophanes (11)
and the pyridine system in 7, the bridge of the [n](1,6)-
pyrenophanes (15) would be expected to also impose a
longitudinal twist, or torsion, around the long axis of the pyrene
system. If the enantiomers of such a pyrenophane could be
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Scheme 4. Reaction of Tetrabromide 22a with Na2S/Al2O3
Scheme 5. Attempted Intramolecular McMurry Reaction of
28a
Tetrabromides 22b (9-carbon tether) and 22c (10-carbon
tether) were synthesized from 1,8-nonadiyne (19b) and 1,9-
decadiyne (19c), respectively, according to the approach used
for 22a (Scheme 3). For 22b, some of the reagents were
different, but there was little change in the yields. However, the
outcome of the reactions of 22b and 22c with Na2S/Al2O3
(Scheme 6) was different than that observed for 22a.
Scheme 6. Synthesis of Pyrenophanes 28b,c and 29b,c
Isomers of 25 arise when each benzene ring forms one
CH2SCH2 bridge to the other benzene ring that came from the
same molecule of 22a (an “intramolecular” bridge)10 and one
of the benzene rings that came from a different molecule of 22a
(an “intermolecular” bridge).10 There are two ways in which a
benzene ring can form two “intermolecular” bridges, and these
lead to isomer groups 26 and 27. When each benzene ring
forms two intermolecular CH2SCH2 bridges to one of the
benzene rings originating from a different molecule of 22a, an
isomer of 26 is produced. If the two intermolecular CH2SCH2
bridges from a particular benzene ring are to different benzene
rings of the other molecule of 22a, the product is an isomer of
27. Individual members of each category (see the Supporting
Information) differ in the attachment points of the long bridge
to the common tetrathiacyclophane skeleton. Of course, when
both new CH2SCH2 bridges are intramolecular, the products
are dithiacyclophanes 23a and 24a. Although a small peak
corresponding to [M + 1]+ for these dithiacyclophanes (m/z =
383, 6%) was also observed in the APCI(+) mass spectrum, the
most optimistic interpretation of this observation would be that
only a small proportion of 23a and 24a was generated. Neither
23a nor 24a appears to be strained significantly, so the origin of
the preference for intermolecular reaction at some point during
the coupling reaction is unclear.
In an attempt to circumvent the failed sulfide coupling, the
use of a 2-fold intramolecular McMurry reaction was briefly
investigated. Despite its generally poor record in the synthesis
of [2.2]metacyclophanes,11 intramolecular McMurry reactions
have recently been applied successfully.8c,12 Tetraester 21a was
therefore reduced with LiAlH4, and the crude tetraol was
oxidized with PCC to afford the corresponding tetraaldehyde
(34%, two steps) (Scheme 5). Subjection of this compound to
McMurry reaction conditions13 resulted in the complete
consumption of the starting material, but no mobile
compounds, e.g. 28a and/or 29a (TLC analysis) were formed
during this reaction. At this point, work with an eight-carbon
tether was terminated, and attention was turned to systems
with longer tethers.
For 22b, column chromatography of the crude reaction
mixture afforded a mixture consisting mainly of dithiacyclo-
phanes 23b and 24b. The EI mass spectrum exhibited the
expected molecular ion peak at m/z = 396 (35) and no peaks at
higher mass. The 1H NMR spectrum of this mixture is
consistent with a ca. 3:1 mixture of the two dithiacyclophanes
(ca. 90% purity), but it could not be determined which one was
the major product. For the thioether bridges, the major isomer
gives rise to an AB system (δ 3.98, 3.83, J = 14.8 Hz) and a
singlet (δ 3.80, degenerate AB system). The minor isomer
exhibited two AB systems (δ 3.89, 3.87, J = 14.8 Hz; δ 3.87,
3.74, J = 15.4 Hz). In the aromatic region, signals attributable to
the internal protons of the major and minor isomers were
observed at δ 7.13 and 7.48, respectively, in a ca. 3:1 ratio, along
with a broad singlet at δ 6.84, which is attributable to the
external protons for both isomers. All attempts to purify or
separate 23b and 24b by column chromatography or
crystallization were unsuccessful. In fact, product losses and
decreases in purity accompanied the attempted purifications
and separations. Consequently, the mixture was taken through
the standard five-step series of reactions for the conversion of a
tethered dithiacyclophane into a pyrenophane that has been
used for all of the (2,7)pyrenophanes reported previously by
our group.9,14 This consists of S-methylation, Stevens
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rearrangement, S-methylation, Hofmann elimination, and
cyclodehydrogenation (Scheme 6).
the benzylic protons of the long bridge and one of the benzylic
protons of a thioether bridge. An approximate ratio of 1.7:1 was
determined using these signals. The APCI(+) mass spectrum
showed the expected [M + 1]+ peak at m/z = 411 (39) as well
as a peak at m/z = 821 (21) corresponding to the [M + 1]+
peaks of dimeric tetrathiacyclophanes (cf. 25−27).
Another mixture of compounds was obtained following
column chromatography (single spot by TLC analysis). The 1H
NMR spectrum of this mixture was rather complex but
contained some signals at higher field than δ 0 ppm, which
strongly suggested the presence of [9](1,6)pyrenophane (29b).
No such high field signals would be expected for [9](1,8)-
pyrenophane (28b) because the bridge is not constrained to lie
across the face of the pyrene system, as it is in 29b.
Crystallization of this mixture from hexanes afforded colorless
Like their lower homologues 23b and 24b, 23c and 24c were
found to be somewhat unstable toward chromatography and
general handling under air. To minimize losses during workup
and chromatography, it was found to be practical to filter the
reaction mixture through a plug of Celite and use the crude
material immediately in the subsequent series of steps.
Accordingly, the crude mixture of 23c and 24c was subjected
to an S-methylation/Stevens rearrangement/S-methylation/
Hofmann elimination sequence of reactions. At this point, the
1H NMR spectrum of the product mixture indicated that it
already consisted mainly of the target pyrenophanes 28c and
29c, but with one or more minor (<10%) byproducts. The peak
in the APCI(+) mass spectrum at m/z = 343 (36), two mass
units greater than the [M + 1]+ peak of 28c and 29c, suggested
that the byproducts were cyclophanedienes and/or dihydropyr-
enophanes.16 Whatever the case, treatment of this mixture with
DDQ at room temperature afforded a clean mixture of
[10](1,8)pyrenophane (28c) and [10](1,6)pyrenophane
(29c) in a combined 9% yield over six steps from tetrabromide
22c. Again, all attempts to separate the two products by
chromatography or crystallization were unsuccessful.
1
needles, which were determined by analysis of their H NMR
spectrum (see the Supporting Information) to be a ca. 4:1
mixture of [9](1,8)pyrenophane (28b) and an unidentified
impurity.15 Further crystallizations did not improve the purity.
The aromatic region of the spectrum was dominated by two
singlets (δ 8.29 and 7.94 ppm) and an AX system (δ 8.02, 7.72
ppm, J = 7.8 Hz), which is characteristic of a 1,8-disubstituted
pyrene unit. Since the spectrum was devoid of signals above δ 0
ppm, it was concluded that the impurity was neither
[9](1, 6)pyrenophane ( 29b) nor
a [9](1, 6)-
dihydropyrenophane.16 The 1H NMR spectrum of the material
obtained from the mother liquor (see the Supporting
Information) indicated that it was a ca. 3:8:1 mixture of 28b
and 29b and the same unidentified impurity as before.15
Attempted crystallization of this mixture did not afford a purer
sample of 29b. Signals attributable to 29b include two AX
systems in the aromatic region (δ 8.20, 7.98 ppm, J = 9.2 Hz; δ
8.00, 7.71 ppm, J = 7.6 Hz) and three broad high-field
multiplets centered at δ −0.24 (2 H), −1.30 (4 H), and −1.70
(2 H) ppm. Having identified which aromatic signals
correspond to 28b and 29b, the ratio of these two
pyrenophanes in the crude mixture was estimated to be ca. 3:2.
The benzylic protons of 28b appear as two well-resolved ddd
at δ 3.75 (J = 14.0, 8.5, 4.3 Hz) and 3.14 (J = 14.0, 7.7, 4.4 Hz).
This, in addition to the observation of nine aliphatic signals,
indicated that the bridge in this cyclophane lies to one side of
the plane defined by the pyrene system (cf. the crystal structure
of 28c below) and that the flip of the bridge from one side of
the pyrene system to the other is slow on the NMR time
scale.17 This conformational process interconverts two identical
species. In the spectrum of 29b, the benzylic protons are
observed as two well-resolved ddd at δ 3.73 (J = 13.3, 6.7, 6.7
Hz) and 2.92 (J = 13.4, 6.7, 6.7 Hz), and a total of nine
aliphatic signals (two of them virtually coincident) can be
identified.17 Again, a slow flip of the bridge from one face of the
pyrene system to the other can be inferred, but now the bridge
flip interconverts the two enantiomeric forms of 29b. Thus, at
room temperature, 29b is at least reasonably configurationally
stable. Determination of the energy barrier for the bridge flip,
e.g., using variable-temperature NMR studies, will have to await
the availability of a pure (or purer) sample of 29b.
The ratio of [10](1,8)pyrenophane (28c) to [10](1,6)-
pyrenophane (29c) was determined to be 7:4 by integration of
1
the signals in the aromatic region of the H NMR spectrum
(Supporting Information). The aromatic signals for [10](1,8)-
pyrenophane (28c) were essentially the same as those for 28b
(Δδ < 0.04 ppm), which is not surprising because the pyrene
system in both compounds is expected to be planar. On the
other hand, the aromatic signals for the C2-symmetric
[10](1,6)pyrenophane (29c) (two AX systems: δ 8.34, 8.01
ppm, J = 9.3 Hz; δ 8.04, 7.82 ppm, J = 7.8 Hz) are all at slightly
lower field (Δδ = 0.03−0.14 ppm) than those of 29b. This is
consistent with the trend observed for the [n](2,7)-
pyrenophanes, in which the aromatic protons consistently
move to higher field as the aromatic system becomes more
distorted from planarity.9,14 As with 29b, the bridge of 29c lies
across one face of the pyrene system, which gives rise to some
very high field signals in the 1H NMR spectrum, including two
2 H multiplets centered at δ −1.95 ppm and −2.65 ppm.
Remarkably, the highest field signal appears at more than half a
ppm higher field than the highest field signal observed in any of
the [n](2,7)pyrenophanes (δ −2.10 ppm).9b
1
In the aliphatic region of the H NMR spectrum of the 7:4
mixture of 28c and 29c, the benzylic signals for 29c were
observed as two well-resolved ddd at δ 3.70 (J = 13.1, 11.2, 4.7
Hz) and 3.14 (J = 13.2, 4.4, 4.4 Hz). In contrast, those of 28c
appeared as very broad singlets, which were suggestive of a
conformational process near coalescence. A DNMR experiment
(Figure S1, Supporting Information) was performed (toluene-
d8 solution), and an energy barrier of ΔG⧧ = 14.9 0.2 kcal/
mol for the process was determined (Tc = 325 K, νAB = 297.7
Hz).18 It was also observed that the benzylic signals of 29c
gradually lost resolution upon warming to 366 K (the limit of
the instrument) but had not yet assumed the appearance of the
signals for 28c at 278 K (45 K below coalescence). If 29c is
assumed to be ≈100 K below coalescence, this would
correspond to an energy barrier of ΔG⧧ ≈ 22 kcal/mol.
Moving to the next higher homologue of the series, reaction
of tetrabromide 22c with Na2S/Al2O3 again afforded a mixture
of the desired dithiacyclophanes 23c and 24c. Standard column
chromatography of the crude reaction mixture afforded a
1
mixture of 23c and 24c of ca. 90% purity (by H NMR
1
analysis) in ca. 40% yield. The H NMR spectrum of the
mixture of 23c and 24c was very similar to that of 23b and 24b,
with the exception of the signals for the internal protons of the
two isomers, which overlapped to give a single broad singlet at
1
δ 7.26. The only signals in the H NMR spectrum of 23c and
24c that exhibited only slight overlap were those due to one of
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However, in view of the report that enantiomerically pure
[9](2,5)pyridinophane (7) retained its optical activity after
prolonged heating at 250 °C,6 it would be quite surprising for
29c to have such a low energy barrier.
The plate-shaped crystal was found to be [10](1,6)-
pyrenophane 29c (Figure 2). The asymmetric unit consists of
The 7:4 ratio (1.75:1) of 28c:29c, where it is clear which
isomer is more abundant, is consistent with the approximate
ratio observed for 23c:24c (1.7:1), where it could not be
determined which isomer is more abundant. The same trend
was observed for the lower homologues 23b:24b (3:1 in favor
of one of them) and 28b:29b (ca. 1.5:1 in favor of 28b). If 23b
and 23c are indeed the major isomers, then it suggests that
there is a significant difference in the rate of SN2 reactions at
the two different types of benzylic bromides in 22b and 22c.
Under this scenario, like benzylic positions of the two aromatic
systems in 22b and 22c will be coupled preferentially. In other
words, the two less hindered positions will be coupled
selectively and the two more hindered positions will be
coupled selectively, resulting in the formation of an excess of
23b and 23c (the precursors to 28b and 28c).
The mixture of [10](1,8)pyrenophane 28c and [10](1,6)-
pyrenophane 29c could not be separated either by crystal-
lization or column chromatography. However, one attempted
crystallization afforded a sample from which two different types
of crystals, a rod and a plate,20 were manually separated under a
microscope. X-ray crystallographic analysis of the rod revealed
that it was [10](1,8)pyrenophane 28c. The asymmetric unit
consists of two closely associated, chemically identical
molecules (one of these is shown in Figure 1). The pyrene
Figure 2. Asymmetric unit of 29c with 50% probability ellipsoids
showing intramolecular C(sp3)−H···π contacts.
a single molecule (Figure 2 and Figures S4,5, Supporting
Information), in which the pyrene system exhibits both an end-
to-end bend and a longitudinal twist. The bend in the pyrene
system cannot be meaningfully described using the bend angle
θ, which is used for (2,7)pyrenophanes. However, a related
angle in (1,6)pyrenophanes, i.e., the smallest angle formed by
the planes defined by C(11)−C(12)−C(21) and C(16)−
C(17)−C(23) in 29c, may prove to be useful provided certain
conditions are met. For comparisons between (1,6)-
pyrenophanes, the torsion angle formed by C(12)−C(21)−
C(23)−C(17) (numbering from 29c) should remain constant.
For meaningful comparisons to (2,7)pyrenophanes to be made,
this torsion angle should be 180°, or very close to it. For 29c,
the torsion angle is 174.5° and the bend angle is 27.3°. This
compares to a θ value of 34.6° for 1,12-dioxa[12](2,7)-
pyrenophane,9e,23 which is the [n](2,7)pyrenophane with the
most gently bent pyrene to have been reported. On the other
hand, the β-angles24 of 29c are 8.5° and 8.0°, which are similar
to those for 1,7-dioxa[7](2,7)pyrenophane (8.2° and 8.7°),9b
which is the [n](2,7)pyrenophane with the most severely bent
pyrene to have been reported. The twist in the pyrene system
in 29c can be quantified by the dihedral angles along the
pathway that connects the two benzylic carbon atoms through
the middle of the pyrene system: C(1)−C(16)−C(23)−
C(26)−C(25)−C(21)−C(11)−C(10). In a completely planar
system, all five of the dihedral angles would be 180°. For 29c,
the angles (starting from the C(1) end of the chain) are
161.43(18)°, −170.51(18)°, 168.73(18)°, −168.70(19)°, and
159.9(2)°. These numbers will now serve as a basis for
comparison to other [n](1,6)pyrenophanes as they become
available.
Figure 1. One of the two chemically identical molecules in the
asymmetric unit of 28c with 50% probability ellipsoids.
A final noteworthy feature of the crystal structure of 29c is
the presence of several short C(sp3)−H···π contacts. Intra-
molecular contacts (2.47 to 2.76 Å) are observed between H-
atoms on contiguous bridge carbon atoms (H(4b), H(5a),
H(6a) and H(7b)) and the centroids of all four of the six-
membered rings of the pyrene system (Figure 2). Comparably
short intermolecular contacts (2.64 to 2.76 Å) exist between
another set of H-atoms on the bridge (H(3b), H(4a) and
H(5b)) and the centroids of three of the four six-membered
rings of the pyrene system of a neighboring molecule (Figure
3). The intermolecular C(sp3)−H···π contacts occur between
molecules of like chirality such that enantiomerically pure,
slipped columns (slippage angle25 = 12.7°) are present in the
system is bowed slightly from planarity, the end-to-end bend
angle (θ)9d,21 being 11.3° and 14.0° for the two molecules in
the asymmetric unit. Considering how little energy is required
to bend pyrene slightly from its planar conformation,22 the
nonplanarity observed here could easily be accounted for
entirely by crystal packing forces. Some short intermolecular
C···H contacts (2.80−2.87 Å) between C(H) atoms and
carbons that form part of the pyrene systems of a neighboring
molecule were observed in the packed unit cell (Figures S2 and
S3, Supporting Information), but no noteworthy C−H···π
interactions (H to aromatic ring centroid) were observed.
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of the rotations for the PAH-based cyclophane 29c is slightly
larger than that reported for the heterocycle-based cyclophane
(+)-7 (+152).6 However, the question of how the rotations
change as the pyrene system becomes increasingly distorted
from planarity will have to await the availability of enantiomeri-
cally pure samples of the lower homologues.
The absorption spectra of 28c and 29c are very similar to
one another. Both cyclophanes exhibit β′, β, and p bands that
are characteristic of simple pyrene systems. Like the [n](2,7)-
pyrenophanes,9e,19 all of these bands are red-shifted (10−32
nm) from those of pyrene. While much of this red shift can be
attributed to substitution of the pyrene system, it is interesting
to note that the p bands of 28c and 29c are significantly red-
shifted from those of [10](2,7)pyrenophane. For example, λmax
for the lowest energy p bands of 28c and 29c are observed at
354 and 356 nm, respectively, whereas those of pyrene and
[10](2,7)pyrenophane are observed at 336 and 341 nm,19
respectively. One noteworthy feature in the spectra of 28c and
29c is the presence of a weak absorption band at 384 and 386
nm, respectively. These are presumably α bands, which have
become less forbidden due to the lowering of the symmetry.
CONCLUSIONS
■
The approach used here for the synthesis of [n](1,6)-
pyrenophanes 29a−c (n = 8−10) met with limited success.
The major source of problems was the Na2S/Al2O3-mediated
self-coupling of tetrabromides 22a−c. In the case of 22a, the
desired dithiacyclophane 24a was not obtained due to
intermolecular reaction. For 22b,c, dithiacyclophanes 23b,c
were certainly formed, but only as components of mixtures of
products. Although they were successfully converted into the
respective [n](1,6)pyrenophanes 29b,c, they could not be
separated from the corresponding [n](1,8)pyrenophanes 28b,c,
and in the case of 29b, an unidentified byproduct using column
chromatography or crystallization. Nevertheless, manual
separation of crystals enabled the determination of the crystal
structures of [10](1,6)pyrenophane 29c and [10](1,8)-
pyrenophane 28c. A small-scale separation of 28c and 29c,
and the two enantiomers of 29c was achieved using chiral
HPLC. This enabled the measurement of the specific rotations,
absorption and CD spectra. Ongoing work is directed toward
the development of an improved synthetic route that leads
exclusively, or at least selectively, to [n](1,6)pyrenophanes.
Access to a series of [n](1,6)pyrenophanes will enable the
study of how the chiroptical properties change with increasing
distortion from planarity.
Figure 3. Packed unit cell of 29c in the crystal showing C(sp3)−H···π
contacts.
crystal. All columns composed of molecules of like chirality
point in the same direction and all columns composed of
molecules of opposite chirality point in opposite directions. All
columns run parallel to the a axis. The prevalence of short
C(sp3)−H···π contacts here and in a recently reported
pyrenophane crystal structure14c may be indicative of this
being a generally important phenomenon for pyrenophanes. As
such, it would be worthwhile to revisit older pyrenophane
structures to check for overlooked C(sp3)−H···π contacts.
Whereas the originally obtained mixture of 28c and 29c
could be used to provide the 1H NMR properties and
(fortunately) the crystal structures of the individual cyclo-
phanes, measurement of the chiroptical properties of 29c
required the separation of this inherently chiral cyclophane
from its achiral isomer 28c in addition to the separation of its
two enantiomers. The use of chiral HPLC was investigated, and
after considerable experimentation, an effective two-stage
procedure was developed. In the first stage, 29b was isolated
(ratio of 28c to (+)-29c = 98.7:1.3 and 99.8:0.2 in two separate
batches) using a Chiralpak AD-H column. The two
enantiomers of 29c were then separated in the second stage
using a Chiralcel OJ-H column. A total of 3−4 mg each of
(+)-29c and (−)-29c with an er of >99.8:0.2 was obtained (see
the Supporting Information). The two enantiomers of 29c
exhibit perfectly complementary CD traces (Supporting
Information), but because of the small quantities of the pure
enantiomers, the specific rotations could not be determined
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under the
protection of nitrogen gas unless otherwise indicated. THF was
freshly distilled from sodium benzophenone ketyl. Dichloromethane
was freshly distilled from calcium hydride. Hexanes were distilled
before use for column chromatography. Flash chromatography was
performed using Silicycle silica gel 60, particle size 40−63 μm.
Compounds on tlc plates were visualized under UV light (254 and 365
nm). Melting points are uncorrected. CD spectra were recorded in a
cell with a 1 mm (0.01 dm) path length at a concentration of 1.7 ×
10−4 M (5.7 × 10−5 g/mL).
Diethyl 4-Bromoisophthalic Acid (17). A mixture of 4-bromo-
m-xylene (16) (25.3 g, 137 mmol), KMnO4 (100 g, 633 mmol), and
water (1.5 L) was heated at reflux for 16 h. The mixture was cooled to
room temperature and suction filtered. The filtrate was acidified by the
addition of aqueous 6 M HCl solution (100 mL), and the white
precipitate formed was isolated by suction filtration and air-dried to
with high precision ([α]24 = −210 20 (c = 0.05 in CHCl3)
D
and [α]24D = +270 40 (c = 0.04 in CHCl3)). The numbers do
just agree within the large experimental error. The magnitude
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afford 17 (18.2 g, 54%) as a white solid: mp 286−290 °C (lit.26 mp =
287 °C); 1H NMR (300 MHz, DMSO-d6) δ = 13.56 (br s, 2 H), 8.37
(d, J = 2.1 Hz, 1 H), 7.99 (dd, J = 8.1, 2.1 Hz, 1 H), 7.90 (d, J = 8.1
Hz, 1 H); 13C NMR (75 MHz, DMSO-d6) δ = 166.8, 166.3, 134.7,
133.8, 133.0, 131.6, 130.5, 125.5.
concentrated under reduced pressure. The residue was subjected to
column chromatography (20:80 ethyl acetate/hexanes) to afford 9c as
a colorless oil (1.35 g, 2.35 mmol, 71%): Rf (20:80 ethyl acetate/
hexanes) 0.21; IR (neat) ν = 2955 (m), 1716 (s), 1366 (w), 1285 (m),
1
1173 (s), 1071 (s), 762 (m) cm−1; H NMR (500 MHz, CDCl3) δ =
8.53 (d, J = 1.4 Hz, 2 H), 8.05 (dd, J = 8.1, 1.6 Hz, 2 H), 7,57 (d, J =
8.1 Hz, 2 H), 4.42 (q, J = 7.2 Hz, 4 H), 4.39 (q, J = 7.2 Hz, 4 H), 2.53
(t, J = 7.1 Hz, 4 H), 1.71−1.68 (m, 4 H), 1.57−1.54 (m, 4 H), 1.42 (t,
J = 6.9 Hz, 6 H), 1.40 (t, J = 7.0 Hz, 6 H); 13C NMR (125 MHz,
CDCl3) δ = 166.1, 165.8, 134.7, 132.8, 132.2, 132.6, 129.4, 129.1, 99.8,
79.6, 61.72, 61.69, 28.8, 28.7, 20.3, 14.7; LCMS [APCl(+)] m/z 575
([M + 1]+, 100), 529 (6); HRMS [CI(+)] calcd for C34H39O8
575.2645, found 575.2643.
Diethyl 4-Bromoisophthalate (18). A mixture of 4-bromoisoph-
thalic acid (17) (13.0 g, 53.2 mmol), concentrated sulfuric acid (4
mL), and absolute ethanol (100 mL) was heated at reflux for 16 h. The
mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was dissolved in diethyl
ether and the resulting solution was washed with water (2 × ), washed
with saturated aqueous NaHCO3 solution (3 × ), washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was subjected to column chromatography (20% diethyl ether/
hexanes) to afford 1827 as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ = 8.40 (d, J = 2.1 Hz, 1 H), 7.95 (dd, J = 8.4, 2.2 Hz, 1 H), 7.73 (d, J
= 8.4 Hz, 1 H), 4.43, (q, J = 7.2 Hz, 2 H), 4.39, (q, J = 7.1 Hz, 2 H),
1.43, (t, J = 7.2 Hz, 3 H), 1.41, (t, J = 7.1 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ = 165.4, 165.0, 134.4, 132.7, 132.0, 129.6, 126.6, 61.9,
61.5, 14.2, 14.1.
1,8-Bis(2,4-bis(ethoxycarbonyl)phenyl)octa-1,7-diyne
(20a). To a degassed mixture of diethyl 4-bromoisophthalate (18)
(12.0 g, 40.0 mmol), Pd(PPh3)Cl2 (560 mg, 0.803 mmol), CuI (152
mg, 0.802 mmol), and 1:1 THF/Et3N (200 mL) was added 1,7-
octadiyne (19a) (2.55 g, 24.0 mmol) in one portion. The reaction was
stirred at 80 °C for 18 h and cooled to room temperature. The
precipitate was removed by suction filtration, and the filter cake was
washed with ethyl acetate (50 mL). The filtrate was washed with
saturated aqueous NH4Cl solution, washed with H2O, washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was subjected to column chromatography (20:80 ethyl
acetate/hexanes) to afford 9a as pale yellow needles (7.33 g, 13.5
mmol, 69%): Rf (20:80 ethyl acetate/hexanes) 0.27; mp (ethanol)
73.0−74.0 °C; IR (neat) ν = 2976 (w), 1718 (s), 1368 (m), 1298 (s),
1259 (s), 1147 (m), 1109 (s), 1009 (s), 764 (s) cm−1; 1H NMR (500
MHz, CDCl3) δ = 8.53 (d, J = 1.4 Hz, 2 H), 8.06 (dd, J = 8.1, 1.6 Hz, 2
H), 7.57 (d, J = 8.1 Hz, 2 H), 4.40 (q, J = 7.1 Hz, 4 H), 4.39 (q, J = 7.1
Hz, 4 H), 2.59−2.57 (m, 4 H), 1.87−1.86 (m, 4 H), 1.41 (t, J = 7.1
Hz, 6 H), 1.40 (t, J = 7.1 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ
166.1, 165.7, 134.7, 132.9, 132.2, 132.6, 129.5, 128.9, 99.2, 79.8, 61.71,
61.69, 28.0, 19.9, 14.67, 14.66; LCMS [APCl(+)] m/z 547 ([M + 1]+,
100), 519 (10); HRMS [EI] calcd for C32H34O8 546.2254, found
546.2245.
1,9-Bis(2,4-bis(ethoxycarbonyl)phenyl)nona-1,8-diyne
(20b). To a degassed solution of diethyl 4-bromoisophthalate (18)
(10.8 g, 35.9 mmol) and 1,8-nonadiyne (19b) (2.16 g, 18.0 mmol) in
Et3N (80 mL) were added Pd(PPh3)2Cl2 (0.50 g, 0.71 mmol) and CuI
(0.60 g, 3.2 mmol). The resulting mixture was heated at reflux for 18 h
and then cooled to room temperature. The reaction mixture was
suction filtered and the filter cake was washed with diethyl ether. The
filtrate was concentrated under reduced pressure and the residue was
subjected to column chromatography (35% diethyl ether/hexanes) to
afford 20b as a colorless solid (8.00 g, 70%): mp (diethyl ether/
hexanes) 63−64 °C; 1H NMR (300 MHz, CDCl3) δ = 8.53 (d, J = 1.7
Hz, 2 H), 8.03 (dd, J = 8.1, 1.8 Hz, 2 H), 7.55 (d, J = 8.1 Hz, 2 H),
4.41 (q, J = 7.2 Hz, 4 H), 4.39 (q, J = 7.1 Hz, 4 H), 2.55−2.53 (m, 4
H), 1.74−1.71 (m, 6 H), 1.42 (t, J = 7.1 Hz, 6 H), 1.41 (t, J = 7.2 Hz, 6
H); 13C NMR (75 MHz, CDCl3) δ = 165.6, 165.2, 134.2, 132.3, 131.7,
131.1, 129.0, 128.5, 99.1, 79.2, 61.2, 28.1, 27.9, 19.7, 14.2; MS [EI] m/
z M+ not observed, 531 (38), 457 (34), 441 (40). Anal. Calcd for
C33H36O8: C, 70.69; H, 6.41. Found: C, 70.74; H, 6.60.
1,10-Bis(2,4-bis(ethoxycarbonyl)phenyl)deca-1,9-diyne
(20c). To a degassed mixture of diethyl 4-bromoisophthalate (18)
(1.00 g, 3.33 mmol), Pd(PPh3)Cl2 (47 mg, 0.067 mmol), CuI (13 mg,
0.067 mol) and 1:1 THF/Et3N (40 mL) was added 1,9-decadiyne
(268 mg, 2.00 mmol) in one portion. The reaction was stirred at 80 °C
for 18 h and cooled to room temperature. The reaction mixture was
suction filtered, and the filter cake was washed with ethyl acetate (50
mL). The filtrate was washed with saturated aqueous NH4Cl solution,
washed with H2O and brine (25 mL), dried over MgSO4, and
1,8-Bis(2,4-bis(ethoxycarbonyl)phenyl)octane (21a). A mix-
ture of diyne tetraester 20a (14.7 g, 27.7 mmol), 10% Pd/C (3.12 g),
and absolute ethanol (200 mL) was stirred vigorously under an
1
atmosphere of H2 (balloon) for 18 h (monitored by H NMR). The
mixture was concentrated under reduced pressure, and the residue was
dissolved in dichloromethane (200 mL). The catalyst was removed by
suction filtration, and the filtrate was concentrated under reduced
pressure. Crystallization of the residue from ethanol afforded 21a as a
white solid (14.4 g, 96%): Rf (dichloromethane) 0.14; mp (ethanol):
96.0−96.5 °C; IR (neat) ν = 2935 (w), 1719 (s), 1364 (w), 1297 (s),
1
1219 (m), 1130 (m), 1067 (m), 1024 (m), 764 (m) cm−1; H NMR
(500 MHz, CDCl3) δ = 8.51 (d, J = 1.6 Hz, 2 H), 8.07 (dd, J = 8.0, 1.4
Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 4.41 (q, J = 7.2 Hz, 4 H), 4.40 (q, J
= 7.2 Hz, 4 H), 3.01−2.98 (m, 4 H), 1.64−1.58 (m, 4 H), 1.43 (t, J =
7.2 Hz, 6 H), 1.42 (t, J = 7.2 Hz, 6 H), 1.38−1.30 (m, 8 H); 13C NMR
(125 MHz, CDCl3) δ = 167.5, 166.3, 149.9, 132.7, 132.1, 131.4, 130.6,
128.6, 61.51, 61.48, 34.9, 32.0, 30.1, 29.8, 14.74, 14.70; LCMS
[APCl(+)] m/z 555 ([M + 1]+, 100), 541 (20), 509 (46); HRMS [EI]
calcd for C32H42O8 554.2880, found 554.2883.
1,9-Bis(2,4-bis(ethoxycarbonyl)phenyl)nonane (21b). A mix-
ture of diyne tetraester 20b (4.19 g, 7.47 mmol), 20% wet palladium
hydroxide on C (Pearlman’s catalyst) (0.803 g), and ethyl acetate (200
mL) was stirred under an atmosphere of hydrogen (hydrogenation
apparatus) for 3 h. The reaction mixture was suction filtered through a
pad of Celite, and the filtrate was concentrated under reduced pressure
to afford tetraester 21b as an oily white solid (4.21 g, 99%): mp (ethyl
1
acetate/heptane) 47−49 °C; H NMR (300 MHz, CDCl3) δ = 8.50
(d, J = 1.8 Hz, 2 H), 8.05 (dd, J = 8.0, 1.9 Hz, 2 H), 7.32 (d, J = 8.1
Hz, 2 H), 4.39 (q, J = 7.1 Hz, 8 H), 3.01−2.96 (m, 4 H), 1.62−1.54
(m, 4 H), 1.41 (t, J = 7.1 Hz, 6 H), 1.40 (t, J = 7.1 Hz, 6 H), 1.34−1.25
(m, 10 H); 13C NMR (75 MHz, CDCl3) δ = 166.9, 165.7, 149.4,
132.1, 131.6, 130.9, 130.1, 128.0, 60.9, 34.4, 31.5, 29.5, 29.3, 14.2; MS
[EI] m/z M+ not observed, 523 (40), 203 (100). Anal. Calcd for
C33H44O8: C, 69.69; H, 7.80. Found: C, 69.44; H, 7.99.
1,10-Bis(2,4-bis(ethoxycarbonyl)phenyl)decane (21c). A
mixture of diynetetraester 20c (9.46 g, 16.5 mmol), 10% Pd/C
(3.74 g), and absolute ethanol (250 mL) was stirred vigorously under
1
an atmosphere of H2 (balloon) for 18 h (monitored by H NMR).
The mixture was concentrated under reduced pressure, and the residue
was dissolved in dichloromethane (200 mL). The catalyst was
removed by suction filtration, and the filtrate was concentrated
under reduced pressure. Crystallization of the residue from ethanol
afforded 21c as a white solid (8.61 g, 90%): Rf (20:80 ethyl acetate/
hexanes) 0.21; mp (ethanol) 77.0−78.0 °C; IR (neat) ν = 2925 (w),
1722 (m), 1289 (w), 1238 (m), 1096 (w), 1071 (w), 1026 (w), 762
(w) cm−1; 1H NMR (500 MHz, CDCl3) δ = 8.49 (d, J = 1.4 Hz, 2 H),
8.05 (dd, J = 8.0, 1.6 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 4.39 (q, J =
7.1 Hz, 4H), 4.38 (q, J = 7.1 Hz, 4 H), 3.00−2.96 (m, 4 H), 1.62−1.56
(m, 4 H), 1.41 (t, J = 7.0 Hz, 6 H), 1.40 (t, J = 7.0 Hz, 6 H), 1.36−1.34
(m, 4 H), 1.27−1.25 (m, 8 H); 13C NMR (125 MHz, CDCl3) δ =
167.6, 166.3, 149.9, 132.7, 132.1, 131.4, 130.7, 128.6, 61.51, 61.48,
34.9, 32.0, 30.1, 30.0, 29.9, 14.74, 14.70; LCMS [APCl(+)] m/z 583
([M + 1]+, 100), 537 (71); HRMS [CI(+)] calcd for C34H47O8
583.3271, found 583.3264.
1,8-Bis(2,4-bis(bromomethyl)phenyl)octane (22a). To a 0 °C
solution of tetraester 21a (5.00 g, 9.02 mmol) in THF (200 mL) was
added dropwise a slurry of LiAlH4 (1.93 g, 50.9 mmol) in THF (20
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mL). The resulting mixture was stirred at room temperature for 16 h
and then quenched by the careful sequential addition of ethyl acetate
(50 mL) and absolute ethanol (25 mL). The resulting mixture was
poured into a 1 M aqueous HCl solution (100 mL) and extracted with
ethyl acetate. The organic layer was washed with brine and
concentrated under reduced pressure to afford a white solid (3.07
g), which was used without purification in the next step. The crude
tetraalcohol exhibited the following spectroscopic data: IR (neat) ν =
3301 (m), 2922 (m), 1467 (w), 1224 (w), 1157 (m), 1049 (s), 1021
g), which was used without purification in the next step. The crude
tetraalcohol exhibited the following spectroscopic data: IR (neat) ν =
3311 (w), 2920 (m), 1465 (w), 1233 (w), 1041 (s), 985 (m), 924 (w),
822 (m), 705 (m) cm−1; 1H NMR (500 MHz, DMSO-d6) δ = 7.33 (s,
2 H), 7.10−7.06 (m, 4 H), 5.08−5.03 (m, 4 H), 4.51 (s, 4 H), 4.45 (s,
4 H), 2.59−2.55 (m, 4 H), 1.50 (br m, 4 H), 1.29−1.18 (m, 12 H);
13C NMR (125 MHz, DMSO-d6) δ = 140.4, 140.1, 138.8, 129.3, 126.6,
125.8, 63.8, 61.5, 32.1, 31.4, 29.93, 29.90, 29.8.
To a well-stirred mixture of the crude tetraalcohol (3.00 g, 7.30
mmol) in dichloromethane (100 mL) was added PBr3 (7.84 g, 29.0
mmol) under N2. The resulting mixture was stirred at room
temperature for 18 h and then H2O (100 mL) was added. The layers
were separated and the organic layer was washed with saturated
aqueous NaHSO4 solution, washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was subjected to
column chromatography (50:50 dichloromethane/hexanes) to afford
22c as a white solid (3.67 g, 76% from 21c): Rf (50:50
dichloromethane/hexanes) 0.57; mp 111.0−113.0 °C; IR (neat) ν =
2926 (m), 2849 (m), 1503 (w), 1465 (m), 1210 (s), 1162 (w), 904
1
(s), 889 (m), 828 (m), 724 (m) cm−1; H NMR (500 MHz, DMSO-
d6) δ = 7.32 (s, 2 H), 7.11−7.05 (m, 4 H), 5.12 (t, J = 5.7 Hz, 2 H),
5.08 (t, J = 5.4 Hz, 2 H), 4.50 (d, J = 5.3 Hz, 4 H), 4.44 (d, J = 5.6 Hz,
4 H), 2.56−2.52 (m, 4 H), 1.49 (br m, 4 H), 1.30 (br s, 8 H); 13C
NMR (125 MHz, DMSO-d6) δ = 140.4, 140.2, 138.8, 129.3, 126.7,
125.8, 63.8, 61.5, 32.1, 31.4, 29.9, 29.8.
To a well-stirred mixture of the crude tetraalcohol (1.00 g, 2.61
mmol) in dichloromethane (50 mL) was added PBr3 (2.89 g, 10.7
mmol). The resulting mixture was stirred at room temperature for 18
h, and H2O (100 mL) was added. The layers were separated, and the
organic layer was washed with saturated aqueous NaHSO4 solution,
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was subjected to column chromatog-
raphy (50:50 dichloromethane/hexanes) to afford 12c as a white solid
(0.773 g, 79% from 21a): Rf (20:80 dichloromethane/hexanes) 0.20;
mp (dichloromethane/hexanes) 142.0−143.0 °C; IR (neat) ν = 2929
(w), 2851 (w), 1464 (w), 1209 (m), 904 (w), 827 (w), 737 (w) cm−1;
1H NMR (500 MHz, CDCl3) δ = 7.35 (d, J = 1.6 Hz, 2 H), 7.27 (dd, J
= 7.9, 1.8 Hz, 2 H), 7.17 (d, J = 7.9 Hz, 2 H), 4.51 (s, 4 H), 4.48 (s, 4
H), 2.72−2.69 (m, 4 H), 1.67−1.61 (m, 4 H), 1.41−1.37 (m, 8 H);
13C NMR (125 MHz, CDCl3) δ = 142.5, 136.23, 136.21, 131.4, 130.7,
129.9, 33.4, 32.5, 31.5, 31.2, 30.1, 29.8. LCMS [APCl(+)] m/z [M +
1]+ not observed; HRMS [CI(+)] calcd for C24H3079Br4 633.9081,
found 633.9087.
1,9-Bis(2,4-bis(bromomethyl)phenyl)nonane (22b). A solu-
tion of tetraester 21b (2.20 g, 3.87 mmol) in THF (75 mL) was added
dropwise to a slurry of LiAlH4 (0.81 g, 0.021 mol) in THF (75 mL),
and the resulting mixture was stirred at room temperature for 6 h. The
reaction was quenched by the careful addition of ethyl acetate (10
mL). The resulting mixture was poured into a 1 M aqueous HCl
solution (100 mL) and extracted with ethyl acetate. The organic layer
was washed with brine and concentrated under reduced pressure to
afford a white solid (1.40 g), which was used without purification in
the next step.
The crude tetraalcohol (0.83 g, 2.1 mmol) was slurried in glacial
acetic acid (30 mL) and 30% HBr in AcOH (3.5 mL, 17 mmol HBr)
was added. The resulting solution was heated at reflux for 16 h. The
reaction mixture was cooled to room temperature and water (50 mL)
was added. The resulting mixture was extracted with diethyl ether and
the organic phase was washed with H2O, washed with aqueous
saturated NaHCO3 solution, washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was subjected
to column chromatography (25% dichloromethane/hexanes) to afford
tetrabromide 22b as a white solid (1.24 g, 83% from 21b): mp
(dichloromethane/hexanes) 112−114 °C; 1H NMR (500 MHz,
CDCl3) δ = 7.35 (d, J = 1.7 Hz, 2 H), 7.27 (dd, J = 7.8, 1.7 Hz, 2
H), 7.18 (d, J = 7.8 Hz, 2 H), 4.51 (s, 4 H), 4.46 (s, 4 H), 2.73−2.68
(m, 4 H), 1.66−1.60 (m, 4 H), 1.39−1.33 (m, 10 H); 13C NMR (125
MHz, CDCl3) δ = 142.2, 135.8, 131.0, 130.2, 129.5, 119.9, 33.0, 32.1,
31.1, 30.8, 29.6, 29.4; MS [EI] m/z M+ not observed, 492 (6), 199
(56), 197 (60), 119 (68), 118 (55). Anal. Calcd for C25H32Br4: C,
46.04; H, 4.95. Found: C, 46.03; H, 4.89.
1,10-Bis(2,4-bis(bromomethyl)phenyl)decane (22c). To a 0
°C solution of tetraester 21c (8.30 g, 14.2 mmol) in THF (250 mL)
was added dropwise a slurry of LiAlH4 (2.97 g, 78.3 mmol) in THF
(20 mL). The resulting mixture was stirred at room temperature for 16
h and then quenched by the careful sequential addition of ethyl acetate
(50 mL) and absolute ethanol (25 mL). The resulting mixture was
poured into a 1 M aqueous HCl solution (100 mL) and extracted with
ethyl acetate. The organic layer was washed with brine and
concentrated under reduced pressure to afford a white solid (5.89
1
(w), 864 (m), 737 (m) cm−1; H NMR (500 MHz, CDCl3) δ = 7.35
(d, J = 1.3 Hz, 2 H), 7.27 (dd, J = 7.9, 1.4 Hz, 2 H), 7.17 (d, J = 7.9
Hz, 2 H), 4.51 (s, 4 H), 4.46 (s, 4 H), 2.72−2.68 (m, 4 H), 1.66−1.60
(m, 4 H), 1.41−1.33 (m, 12 H); 13C NMR (125 MHz, CDCl3) δ =
142.6, 136.22, 136.18, 131.4, 130.7, 129.9, 33.4, 32.5, 31.5, 31.2, 30.1,
29.91, 29.86. LCMS [APCl(+)] m/z [M + 1]+ not observed; HRMS
[CI(+)] calcd for C26H3479Br4 661.9394, found 661.9388.
17,26-Dithia[9.3.3](1,2,4)cyclophane (23b) and 17,26-
Dithia[9.3.3](1,2,4)(1,4,6)cyclophane (24b). To a solution of
tetrabromide 22b (0.57 g, 0.87 mmol) in 10% absolute ethanol/
dichloromethane (400 mL) was added Na2S/Al2O3 (1.4 g, 3.5 mmol)
in several portions over 30 min.28 The resulting mixture was stirred
vigorously at room temperature for 2 h and then suction filtered
through a pad of Celite. The filtrate was concentrated under reduced
pressure, and the residue was subjected to column chromatography
(40:60 dichloromethane/hexanes) to afford a white solid (0.25 g),
which consisted primarily of ca. 3:1 mixture of 23b and 24b: 1H NMR
(300 MHz, CDCl3) (signals attributable to 23b) δ = 7.13 (s, 2 H),
6.84 (s, 4 H), 3.98 (d, J = 14.8 Hz, 2 H), 3.83 (d, J = 14.8 Hz, 2 H),
3.80 (s, 4 H), 2.85−2.75 (m, 2 H), 2.23−2.12 (m, 2 H), 1.58−0.71
(m, 16 H); (signals attributable to 24b) δ = 7.48 (s, 2 H), 6.84 (s, 4
H), 3.89 (d, J = 14.8 Hz, 2 H), 3.87 (d, J = 14.8 Hz, 2 H), 3.87 (d, J =
15.4 Hz, 2 H), 3.74 (d, J = 15.4 Hz, 2 H), 2.77−2.70 (m, 2 H), 2.31−
2.21 (m, 2 H), 1.58−0.71 (m, 16 H); 13C NMR (75 MHz, CDCl3) δ =
139.2, 134.3, 134.0, 132.3, 132.2, 129.7, 127.5, 127.1, 126.9, 39.2, 38.7,
38.6, 30.5, 29.2, 27.4, 27.3, 26.2, 25.7, 25.3, 24.3, 22.8; MS [EI(+)] m/
z 396 (M+, 35), 148 (28), 105 (27).
18,27-Dithia[10.3.3](1,2,4)cyclophane (23c) and 18,27-
Dithia[10.3.3](1,2,4)(1,4,6)cyclophane (24c). To a solution of
tetrabromide 22c (1.00 g, 1.51 mmol) in 10% absolute ethanol/
dichloromethane (250 mL) was added Na2S/Al2O3 (2.33 g, 6.04
mmol).28 The resulting mixture was stirred at room temperature for 16
h and then suction filtered. The filtrate was concentrated under
reduced pressure, and the residue was subjected to column
chromatography (50:50 dichloromethane/hexanes) to afford a white
solid, which consisted primarily of a ca. 1.7:1 mixture of 23c and 24c
1
(254 mg, 41%): Rf (50:50 dichloromethane/hexanes) 0.43; H NMR
(500 MHz, CDCl3) (signals attributable to 23c) δ = 7.26 (s, 2 H),
6.87−6.81 (m, 4 H), 4.05 (d, J = 14.8 Hz, 2 H), 3.84−3.78 (m, 6 H),
2.69 (ddd, J = 14.9, 10.7, 5.3 Hz, 2 H), 2.23 (ddd, J = 14.8, 11.1, 4.9
Hz, 2 H), 1.74−1.67 (m, 2 H), 1.76−0.96 (m, 16 H); (signals
attributable to 24c) δ = 7.26 (s, 2 H), 6.87−6.81 (m, 4 H), 3.88 (d, J =
14.8 Hz, 2 H), 3.84−3.78 (m, 6 H), 2.76 (ddd, J = 15.0, 10.2, 3.5 Hz, 2
H), 2.29 (ddd, J = 15.0, 7.4, 3.1 Hz, 2 H), 1.76−0.96 (m, 16 H); 13C
NMR (125 MHz, CDCl3) δ = 139.2, 138.1, 135.4, 134.7, 132.9, 132.5,
128.8, 128.5, 127.7, 127.5, 39.1, 39.0, 31.3, 30.2, 28.8, 28.1, 27.9, 27.54,
27.47, 27.2, 27.08, 27.05; LCMS [APCl(+)] m/z 839 (Mdimer + 19]+,
21), 821 (Mdimer + 1]+, 21), 427 ([M + 17]+, 100), 411 ([M + 1]+, 39);
HRMS [EI] calcd for C26H34S2 410.2102, found 410.2110.
[9](1,8)Pyrenophane (28b) and [9](1,6)Pyrenophane (29b).
To a solution of dithiacyclophanes 23b and 24b (0.25 g, max. 0.63
64
dx.doi.org/10.1021/jo201013q | J. Org. Chem. 2012, 77, 57−67

The Journal of Organic Chemistry
Article
mmol) in dichloromethane (15 mL) was added (MeO)2CHBF4
(Borch reagent)29 (0.5 g, 3 mmol) slowly over 5 min by syringe.
The resulting mixture was stirred for 1 h, and the solvent was removed
under reduced pressure. To the resulting oily residue was added 4:1
methanol/water (2 mL), and after the mixture was stirred for a few
minutes, the solvent was removed under reduced pressure. The
resulting oily solid was suspended in THF (20 mL), and to this
mixture was added t-BuOK (0.60 g, 5.3 mmol). The reaction mixture
was stirred at room temperature for 14 h, and water (1 mL) was
added. The solvent was removed under reduced pressure, and the
residue was taken up in dichloromethane (60 mL). The resulting
solution was washed with aqueous 1 M HCl solution, water, and brine,
dried over MgSO4, and concentrated under reduced pressure to afford
a foamy white solid (0.101 g).
To a solution of this solid (0.060 g) in dichloromethane (15 mL)
was added (MeO)2CHBF4 (Borch reagent)29 (0.4 g, 2 mmol) slowly
over 5 min by syringe. The resulting mixture was stirred for 1 h, and
the solvent was removed under reduced pressure. The oily brown
residue was suspended in 1:1 THF/t-BuOH (40 mL), and t-BuOK
(0.51 g, 4.5 mmol) was added in one portion. The reaction mixture
was stirred at room temperature for 14 h, and the solvent was removed
under reduced pressure. The residue was taken up in dichloromethane
(50 mL) and water (50 mL), and the layers were separated. The
organic layer was washed with aqueous 1 M HCl solution, water, and
brine, dried over MgSO4, and concentrated under reduced pressure to
afford a yellow-brown oil.
This oil was dissolved in benzene (20 mL), and DDQ (0.100 g,
0.441 mmol) was added. The reaction mixture was heated at reflux for
1 h and cooled to room temperature, and the solvent was removed
under reduced pressure. The residue was subjected to column
chromatography (10% dichloromethane/hexanes) to afford a mixture
of 28b, 29b and an unidentified impurity as a white solid: 13C NMR
(75 MHz, CDCl3) δ = 137.4, 130.1, 129.4, 129.2, 128.7, 128.4, 127.3,
127.1, 126.9, 126.7, 126.2, 126.1, 126.0, 125.4, 124.9, 124.7, 124.0,
123.9, 123.63, 123.55, 55.4, 33.2, 33.1, 32.9, 32.4, 31.0, 30.91, 30.87,
30.23, 30.15, 29.6, 29.0, 27.9, 27.5, 27.0, 24.7, 24.1; MS [EI] m/z (%):
326 (M+, 79), 324 (31), 253 (32), 241 (43), 239 (37), 228, (100), 215
(35). Crystallization of this mixture from hexanes afforded white
needles that consisted of a ca. 4:1 mixture of 28b and the unidentified
impurity: 1H NMR (300 MHz, CDCl3) (signals attributable to 28b) δ
= 8.29 (s, 2 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.94 (s, 2 H), 7.72 (d, J = 7.7
Hz, 2 H), 3.75 (ddd, J = 14.0, 8.5, 4.3 Hz, 2 H), 3.14 (ddd, J = 14.0,
7.7, 4.4 Hz), 2.21−2.08 (m, 2 H), 1.37−1.24 (m, 2 H), 1.08−0.96, (m,
2 H), 0.76−0.61 (m, 2 H), 0.56−0.43 (m, 2 H), 0.45−0.33 (m, 2 H),
0.17−0.05 (m, 2 H). The mother liquor was concentrated under
reduced pressure to afford a ca. 8:3:1 mixture of 29b, 28b, and the
unidentified impurity: 1H NMR (300 MHz, CDCl3) (signals
attributable to 29b) δ 8.20 (d, J = 9.2 Hz, 2 H), 8.00 (d, J = 7.8
Hz, 2 H), 7.98 (d, J = 9.2 Hz, 2 H), 7.71 (d, J = 7.6 Hz, 2 H), 3.73
(ddd, J = 13.3, 6.7, 6.7 Hz, 2 H), 2.92 (ddd, J = 13.4, 6.7, 6.7 Hz, 2 H),
1.64−1.52 (m, 2 H), 1.28−1.14 (m, 2 H), 0.42−0.29 (m, 2 H), −0.18
to −0.30 (m, 2 H), −1.25 to −1.35 (m, 4 H), −1.64 to −1.75 (m, 2
H).
[10](1,8)Pyrenophane (28c) and [10](1,6)Pyrenophane
(29c). To a solution of dithiacyclophanes 23c and 24c (254 mg,
max. 0.620 mmol) in dichloromethane (10 mL) was added
(MeO)2CHBF4 (Borch reagent)29 (457 mg, 2.74 mmol) slowly over
5 min by syringe. The resulting mixture was stirred for 1 h, and the
solvent was removed under reduced pressure. To the resulting residue
was added ethyl acetate (6 mL), and this mixture was stirred
vigorously for 5 min. The supernatant was decanted, and the residue
was dried under vacuum. The residue was slurried in THF (15 mL),
and t-BuOK (352 mg, 3.12 mmol) was added in one portion. The
reaction was stirred overnight and then quenched by the addition of
saturated aqueous NH4Cl solution (1 mL). The reaction mixture was
concentrated under reduced pressure, and the residue was filtered
through a plug of Celite (dichloromethane) to afford a yellow oil (253
mg).
reagent)29 (269 mg, 1.61 mmol), and the resulting mixture was
stirred at room temperature for 4 h. The solvent was removed under
reduced pressure, and the residue was suspended in THF (15 mL). To
this mixture was added t-BuOK (253 mg, 2.23 mmol) in one portion,
and the resulting mixture was sonicated for 1 h. The mixture was then
stirred at room temperature for 16 h. The solvent was removed under
reduced pressure and the residue was subjected to column
chromatography (25:75 dichloromethane/hexanes) to yield a mixture
of compounds consisting mainly of pyrenophanes 28c and 29c (1H
NMR analysis) as a colorless oil (85 mg): Rf (20:80 dichloromethane/
hexanes) 0.50; LCMS [APCl(+)] m/z 343 ([Mcyclophanedienes + 1]+, 36),
342 (25), 341 ([Mpyrenophanes + 1]+, 78), 340 (65).
To a well-stirred solution of the product mixture from the previous
reaction in degassed benzene (8 mL) was added a solution of DDQ
(227 mg, 0.714 mmol) in degassed benzene (2 mL). The reaction
mixture turned green, then orange, then dark red within 10 min. The
mixture was stirred overnight at room temperature and then
concentrated under reduced pressure. The residue was subjected to
column chromatography (10:90 dichloromethane/hexanes) to afford a
7:4 mixture of pyrenophanes 28c and 29c as a white solid (43 mg, 0.16
mmol, 9%, six steps from tetrabromide 22c): Rf (10:90 dichloro-
1
methane/hexanes) 0.14; mp 140.0−143.5 °C; H NMR (500 MHz,
CDCl3) (signals attributable to 28c) δ = 8.33 (s, 2 H), 8.06 (d, J = 7.7
Hz, 2 H), 7.96 (s, 2 H), 7.76 (d, J = 7.7 Hz, 2 H), 3.76 (v br s, 2 H),
3.18 (v br s, 2 H), 2.08 (v br s, 2 H), 1.75 to −0.16 (m, 14 H); 1.15−
1.09 (m, 10 H), 1.06−1.01 (m, 12 H), 0.58−0.51 (m, 2 H), 0.80 to
−0.12 (m, 4 H); (signals attributable to 29c) δ = 8.34 (d, J = 9.3 Hz, 2
H), 8.04 (d, J = 7.5 Hz, 2 H), 8.01 (d, J = 9.2 Hz, 2 H), 7.82 (d, J = 7.8
Hz, 2 H), 3.70 (ddd, J = 13.1, 11.2, 4.7 Hz, 2 H), 3.14 (ddd, J = 13.2,
4.4, 4.4 Hz, 2 H), 1.98−1.91 (m, 2 H), 1.17−0.79 (m, 6 H), 0.58−0.51
(m, 2H), −0.01 to −0.14 (m, 2 H), −1.94 to −2.00 (m, 2 H), −2.61
to −2.68 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ = 138.1, 137.0,
130.4, 129.92, 129.87, 129.2, 127.7, 126.8, 126.5, 126.3, 125.5, 125.1,
124.9, 124.2, 123.7, 33.5, 32.3, 31.5, 30.7, 30.4, 30.1, 29.78, 29.77,
28.33, 28.27, 28.0, 25.9; LCMS [APCl(+)] m/z 341 ([M + 1]+, 100),
340 (29); HRMS [CI(+)] calcd for C26H29 341.2269, found 341.2263.
Two samples of 28c and 29c remaining from multiple attempted
crystallizations and chromatographic separations were subjected to a
two-stage preparative chiral HPLC protocol. In the first stage, 28c was
isolated (Chiralpak AD-H column, 2 × 15 cm, 30% methanol/CO2,
100 bar, 65 mL/min, 280 nm). The two enantiomers of 29c were then
separated in the second stage (Chiralcel OJ-H column, 2 × 15 cm,
30% methanol/CO2, 100 bar, 65 mL/min, 280 nm). Peak 1 (3 mg
combined) was found to be (−)-29c: [α]24D = −210 20 (c = 0.05 in
CHCl3); UV−vis (CHCl3) λmax (log ε) 274 (4.3), 284 (4.4), 326 (sh,
4.0), 340 (4.3), 356 (4.5), 386 (3.5) nm; CD (CHCl3) [θ]283 = −2.4 ×
105 deg·cm2·dmol−1. Peak 2 (4 mg combined) was found to be
(+)-29c: [α]24 = +270 40 (c = 0.04 in CHCl3); UV−vis (CHCl3)
D
λmax (log ε) 274 (4.3), 284 (4.4), 326 (sh, 4.0), 340 (4.3), 356 (4.5),
386 (3.5) nm; CD (CHCl3) [θ]283 = +2.0 × 105 deg·cm2·dmol−1. Peak
3 was found to be 28c: UV−vis (CHCl3) λmax (log ε) 274 (3.9), 284
(4.1), 324 (sh, 3.6), 338 (4.0), 354 (4.1), 384 (2.8) nm.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 20a−c, 21a−c,
22a−c, 23b+24b, 23c+24c, 28b+29b, and 28c+29c. DNMR
spectra for compounds 28c and 29c. Mass spectra for
compounds 23c+24c and 25−27. Structures of possible
isomers for compounds 25−27. Other views of 28c and 29c
in the crystal. CIF files for 28c and 29c. HPLC traces for 28c
and 29c before and after separation. CD spectra of (+)-29c and
(−)-29c. This material is available free of charge via the
Internet at http://pubs.acs.org.
To a solution of this yellow oil (253 mg, 0.620 mmol) in
dichloromethane (10 mL) was added (MeO)2CHBF4 (Borch
65
dx.doi.org/10.1021/jo201013q | J. Org. Chem. 2012, 77, 57−67

The Journal of Organic Chemistry
Article
(10) The terms “intermolecular” and “intramolecular” are used here
solely to describe how the CH2SCH2 bridges connect the two units
derived from 22a and not to describe the nature of the reactions that
lead to their formation. Once one intermolecular CH2SCH2 bridge has
formed, all subsequent reactions leading to the formation of CH2SCH2
bridges are necessarily intramolecular, regardless of whether that
bridge connects two benzene rings originating from the same molecule
of 22a or two benzene rings originating from the different molecules
of 22a.
(11) (a) Mitchell, R. H.; Weerawarna, S. A Tetrahedron Lett. 1986,
27, 453−456. (b) Yamato, T.; Fujita, K.; Tsuzuki, H. J. Chem. Soc.,
Perkin Trans. 1 2001, 2089−2097. (c) Sahade, D. A.; Tsukamoto, K.;
Thiemann, T.; Sawada, T.; Mataka, S. Tetrahedron 1999, 55, 2573−
2580.
(12) An Al-pinacol/reduction protocol has also been reported to be
effective: Chifuku, K.; Sawada, T.; Kihara, T.; Shimojo, K.; Sonoda, H.;
Kuwahara, Y.; Shosenji, H.; Ihara, H. Synlett 2008, 3153−3156.
(13) Lenoir, D. Synthesis 1977, 553−554.
(14) (a) Bodwell, G. J.; Miller, D. O.; Vermeij, R. J. Org. Lett. 2001, 3,
2093−2096. (b) Zhang, B.; Manning, G. P.; Dobrowolski, M. A.;
Cyranski, M. K.; Bodwell, G. J. Org. Lett. 2008, 10, 273−276.
́
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (+1) 709-864-8406. Fax: (+1) 709-864-3702. E-mail:
gbodwell@mun.ca.
ACKNOWLEDGMENTS
■
Financial support of this work from the Natural Sciences and
Engineering Research Council (NSERC) of Canada (G.J.B.)
and the National Science Foundation (Grant No. CHE-
0936862) (R.A.P.) is gratefully acknowledged.
REFERENCES
■
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flipping is slow. For odd values of n, (n + 1)/2 aliphatic signals are
expected when bridge flipping is fast on the NMR time scale and n
aliphatic signals are expected when bridge flipping is slow.
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is clearly not something that can be relied upon as a means of
separation.
(21) Strictly speaking, the angle θ was defined to describe the bend of
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as those in the (2,7)pyrenophanes, and the magnitude of the bend is
small.
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(23) Yao, T.; Yu, H.; Vermeij, R. J.; Bodwell, G. J. Pure. Appl. Chem.
2008, 80, 535−548.
(24) This β angle is directly analogous to the one used to describe
[n]paracyclophanes. See: Keehn, P. M. in ref 1b, Ch. 3.
(25) The slippage angle is defined as 90° minus the smallest angle
between the mean plane for [C(14), C(15), C(19), C(20), C(25),
C(26)] and the mean plane for [C(25), C(26), C(25′) and C(26′)]
with C(25′) and C(26′) generated by the operation (1 + x, y, z). For
29c, the slippage angle is 90.0° − 77.3° = 12.7°.
(26) Schopff, M. Ber. Dtsch. Chem. Ges. 1891, 24, 3771−3784.
̈
(27) Igarashi, S.; Kimura, T.; Naito, R.; Hara, H.; Fujii, M.; Koutoku,
H.; Oritani, H.; Mase, T. Chem. Pharm. Bull. 1999, 47, 1073−1080.
(28) Bodwell, G. J.; Houghton, T. J.; Koury, H. E.; Yarlagadda, B.
Synlett 1995, 751−752.
(29) For the original report of this reagent, see: Borch, R. F. J. Org.
Chem. 1969, 34, 627−629. For our modified procedure, see ref 9e.
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