Macrocyclization and molecular interlocking via Mitsunobu alkylation: Highlighting the role of C-H...O interactions in templating

Article abstract of DOI:10.1021/ol991289w

(Formula presented) A series of diimide-based macrocycles have been prepared using Mitsunobu-mediated alkylation as the macrocyclization step. These macrocycles could not be incorporated into [2]catenanes using previously established building blocks and coupling methodology. However, when one of the macrocycle syntheses was conducted in the presence of a dinaphtho crown ether, catenane formation was achieved. This result is discussed in terms of the ability of the components to establish intermolecular C-H...O hydrogen-bonding contacts.

Full text of DOI:10.1021/ol991289w

ORGANIC
LETTERS
2
000
Vol. 2, No. 4
49-452
Macrocyclization and Molecular
Interlocking via Mitsunobu Alkylation:
Highlighting the Role of C−H‚‚‚O
Interactions in Templating
4
Jimmi G. Hansen,†,‡ Neil Feeder, Darren G. Hamilton, Maxwell J. Gunter,
†
†
†,§
‡
,†
Jan Becher, and Jeremy K. M. Sanders*
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K.
jkms@cam.ac.uk
Received November 30, 1999
ABSTRACT
A series of diimide-based macrocycles have been prepared using Mitsunobu-mediated alkylation as the macrocyclization step. These macrocycles
could not be incorporated into [2]catenanes using previously established building blocks and coupling methodology. However, when one of
the macrocycle syntheses was conducted in the presence of a dinaphtho crown ether, catenane formation was achieved. This result is discussed
in terms of the ability of the components to establish intermolecular C−H‚‚‚O hydrogen-bonding contacts.
In this Letter we describe the preparation of three macro-
cycles derived from aromatic diimides and poly(ethylene
glycol) linkers and of a [2]catenane formed when the
synthesis of one of the macrocycles is conducted in the
presence of a complementary preformed dinaphtho crown
ether. The achievement of macrocyclization and interlocking
by means of Mitsunobu alkylation of aromatic diimides
represents the third covalent means by which to prepare an
interlocked system containing such components, in addition
to Glaser-Hay coupling of terminal acetylenes and Grubbs’
olefin metathesis;1 a catenane of this type has also been
assembled via zinc(II)-bipyridyl ligation.3
Our initial aim in preparing the diimide-polyether macro-
cycles described here was to attempt to reverse the roles of
the linkers in our original [2]catenane 3, assembled by
coupling two units of acetylenic diimide 2 in the presence
of dinaphtho crown 1 (Figure 1). The preformed diimide
macrocycle 4 was intended to act as a template for cyclo-
dimerization of acetylenic aromatic diether 5 to give [2]ca-
tenane 6, a structural isomer of 3. However, as we report
below, such cyclizations failed to provide any interlocked
products. In fact, the lack of evidence for any interaction
between 4 and 5 led to a reconsideration of the molecular
design, and ultimately to the selection of an alternative
method for achieving molecular interlocking of diimide-
derived macrocycles such as 4.
,2
†
University of Cambridge.
Department of Chemistry, Odense University, Campusvej 55, DK-5230
‡
Odense M, Denmark.
§
Retrosynthetic analysis of 4 reveals several options. The
Department of Chemistry, University of New England, Armidale, New
South Wales 2351, Australia.
route we selected acknowledges the fact that condensation
(
1) Hamilton, D. G.; Davies, J. E.; Prodi, L.; Sanders, J. K. M. Chem.
Eur. J. 1998, 4, 608-620.
2) Hamilton, D. G.; Feeder, N.; Teat, S. J.; Sanders, J. K. M. New J.
Chem. 1998, 22, 1019-1021.
(
(3) Try, A. C.; Harding, M. M.; Hamilton, D. G.; Sanders, J. K. M. Chem.
Commun. 1998, 723-724.
1
0.1021/ol991289w CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/26/2000

an attribute that may indirectly favor macrocyclization by
ensuring that only a very low concentration of diimide is
maintained in solution. In the cases of preparation of
macrocycles 4 and 10, from the reaction of diimide 9 with
diols 7 and 8, respectively, reaction progress could be
conveniently monitored by following the disappearance of
the suspended diimide (Scheme 2).
Scheme 2
Figure 1. Successful and unsuccessful [2]catenane syntheses.
reactions of primary amines with aromatic dianhydrides
proceed well. However, in our experience macrocyclization
4
using amine-anhydride condensation is problematical and
we therefore targeted Mitsunobu alkylation of aromatic
diimides with primary alcohols for the cyclization reaction
since alkylation of aromatic diimides with simple terminal
2
alcohols proceeds rapidly and efficiently. Tetraethylene
Preparation of bis-naphthalene diimide macrocycle 12
proved most problematical, a fact attributed to the extreme
insolubility of diimide 11 in THF. During previous prepara-
tions of 11 we assayed its purity via derivatization by
glycol-substituted pyromellitic and naphthalene diimide
derivatives 7 and 8 were prepared in typical yields from the
appropriate dianhydrides and 2-(2-(2-(2-aminoethoxy)ethoxy)-
ethoxy)ethanol, itself available in three simple steps from
tetraethylene glycol (Scheme 1).5
2
Mitsunobu alkylation. The results indicated that the diimide
,6
was 80% pure, though it is possible that different batches of
material may vary in their homogeneity. This may contribute
to the extremely low isolated yields of 12, though it should
be noted that continuous sonication of the reaction mixture
was necessary in order to obtain even this modest success.
Likewise, only traces of the mixed diimide macrocycle 10
could be obtained from diol 7 and naphthalene diimide 11;
this latter route was not explored further since 10 could be
obtained in comparable yield to 4 via the alternative route
of cyclizing diol 8 with pyromellitic diimide 9.
Scheme 1
Using the coupling protocol previously employed in the
synthesis of [2]catenane 3, we attempted to achieve cyclo-
dimerization and interlocking of bis-acetylene diether 5 with
(4) Hansen, J. G.; Bang, K. S.; Thorup, N.; Becher, J. Eur. J. Org. Chem.,
in press.
Macrocyclizations were performed in dry THF containing
(5) Ashton, P. R.; Huff, J.; Menzer, S.; Parsons, I. W.; Preece, J. A.;
2
.5 equiv of PPh
3
, at 5 mM concentration of diol and diimide,
Stoddart, J. F.; Tolley, M. S.; White, A. J. P.; Williams, D. J. Chem. Eur.
J. 1996, 2, 31-44.
by dropwise addition of DEAD (2.5 equiv). The aromatic
diimides 9 and 11 are only very sparingly soluble in THF,
(
6) Lebeau, L.; Oudet, P.; Mioskowski, C. HelV. Chim. Acta 1991, 74,
1697-1706.
450
Org. Lett., Vol. 2, No. 4, 2000

1
diimide macrocycles 4 and 10. Notably, prior to addition
structures of related systems, but we are dealing with rather
weak interactions which might readily be swamped by
competing packing forces during crystal growth. However,
a conclusion that arises as a consequence of acceptance of a
potential role for C-H‚‚‚O interactions is that a prerequisite
for efficient binding would be to position “acidic” hydrogen
atoms near suitable acceptors, such as the oxygen atoms of
a polyether chain. Our approach to [2]catenane 6 thus
appears flawed: the methylene groups of acetylenic diether
component 5 are adjacent to an electron-rich system not an
electronegative one that might impart the requisite acidity
on the hydrogen atoms and aid hydrogen bond formation
and complexation.
A logical conclusion to draw from the above discussion
is that the benzene and naphthalene diimide diols 7 and 8,
which possess the requisite “acidic” methylene groups, may
be viable catenane precursors: Mitsunobu macrocyclization
of these materials with the appropriate aromatic diimides, 9
or 11, in the presence of the dinaphtho crown 1 might lead
to catenane formation. Promisingly, the formation of [2]ca-
tenanes could be detected by mass spectrometry from
reactions of 7 with 9, or 8 with 11, in the presence of 1
equiv of crown 1. However, the limited success of the latter
reaction is doubtless hampered by the same solubility
problems that plagued the synthesis of the free diimide
macrocycle 12; the lack of significant [2]catenane production
from the former reaction is harder to explain other than by
concluding that binding between these components is very
weak. In stark contrast with these results is the isolation of
a 17% yield of [2]catenane 13 as a deep red crystalline
material from the reaction, under identical conditions, of diol
8 with diimide 9 in the presence of 1 (Scheme 3).
of the copper salts used to promote coupling of the terminal
acetylenes, the DMF solutions containing 1:2 molar ratios
of macrocycle to bis-acetylene did not exhibit the strong
solution colors that we have come to expect from mixtures
of electron-rich and electron-deficient components of this
type. Regardless, the copper salts were added and the reaction
mixture treated and worked up as previously reported. No
evidence for the formation of interlocked material was found.
The reactions were repeated in chloroform using a modified
protocol for the coupling reaction, but again no catenane
formation was observed.7
While we cannot rule out some unfavorable interaction
geometry that prevents cyclodimerization of 5 through the
cavity of the diimide macrocycles, the lack of solution
colorationsthe signature of co-facial interaction in systems
of this typessuggests that little or no binding occurs.
Although strong solution coloration arising from donor-
acceptor interactions is an indicator of association between
aromatic diethers and acceptors, there is increasing suspicion
that such interactions may not be the primary driving force
for binding. Numerous weak C-H‚‚‚O interactions have long
been recognized as important structural control elements in
the solid-state organization of charged catenanes based on
electron-deficient bipyridinium systems and electron-rich
aromatic diethers,8 and recently relative weightings for the
various noncovalent interactions operating within these
1
3
,9
10
systems have been suggested: synthetic and computational
study indicated that, for bipyridinium based catenanes, the
C-H‚‚‚O interactions between “acidic” bipyridinium protons
and oxygen atoms in the polyether chains of the crown
outweighed the contribution from stacking of the comple-
mentary π-systems by a factor of around 4 to 1.
Perhaps it is likely that our successful synthesis of
[2]catenane 3 also has rather more to do with favorable
Scheme 3. A [2]Catenane via Mitsunobu Alkylation
C-H‚‚‚O contacts than with establishing donor-acceptor
interactions. The methylene group of the diimide component
of this preparation is situated next to an electron-deficient
imide nitrogen, satisfying the criterion of activation of a C-H
bond by a neighboring “electronegative” group.11 Notably,
analysis of the solid-state structure of 3 reveals the presence
of a relatively short and strong C-H‚‚‚O hydrogen-bonding
contact between a diimide methylene hydrogen and the
central oxygen atom of the crown polyether chain (Figure
1
2
2
). Similar contacts are not present in the solid-state
Substantial, deep-red crystals of [2]catenane 13 could
readily be grown from chloroform/methanol mixtures. For
(
7) Anderson, H. L.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1
995, 2223-2229.
8) Ashton, P. R.; Goodnow, T. T.; Kaifer, A. E.; Reddington, M. V.;
1
(
Slawin, A. M. Z.; Spencer, N.; Stoddart, J. F.; Vicent, C.; Williams, D. J.
Angew. Chem., Int. Ed. Engl. 1989, 28, 1396-1399.
(9) Anelli, P. L.; Ashton, P. R.; Ballardini, R.; Balzani, V.; Delgado,
M.; Gandolfi, M. T.; Goodnow, T. T.; Kaifer, A. E.; Philp, D.; Pietraszk-
iewicz, M.; Prodi, L.; Reddington, M. V.; Slawin, A. M. Z.; Spencer, N.;
Stoddart, J. F.; Vicent, C.; Williams, D. J. J. Am. Chem. Soc. 1992, 114,
1
93-218.
10) Houk, K. N.; Menzer, S.; Newton, S. P.; Raymo, F. M.; Stoddart,
J. F.; Williams, D. J. J. Am. Chem. Soc. 1999, 121, 1479-1487.
11) Steiner, T. Chem. Commun. 1997, 727-734.
(
Figure 2. C-H‚‚‚O contacts in the solid-state structure of 3.
Org. Lett., Vol. 2, No. 4, 2000
(
451

the first time in our experience of catenanes the structural
solution was obtained using a laboratory X-ray source and
was refined to a final R value of 7.1% despite some disorder
in one of the polyether links (see Supporting Information
for details of the structural solution and refinement).
The [2]catenane structure contains only molecules in which
the naphthalene diimide unit is located inside the crown
macrocycle; the interaction of this diimide with the electron-
rich aromatic diethers is known to be rather stronger than
that with pyromellitic diimides. Such a solid-state structural
preference, presumably directed by comparative interaction
energetics during the crystallization process, has been found
in the solid-state structures of related systems. A familiar
stacked array of complementary electron-rich and electron-
deficient components is maintained (Figure 3), these units
contrast, both diimide frameworks of 13 are substantially
bowed. There are angles of around 5° between the mean
planes of the imide rings within each diimide unit; the
N-methylene bonds are bent by 5-10° away from copla-
narity.
Long axes drawn through the four stacked catenane
components show that the two naphthalene diethers sit
squarely one upon the other (twist angle 1°) while those of
the diimides define an angle of 54°. However, examination
of the relationship of each diimide to its neighboring
naphthalene diethers reveals that each of the distinct diimides,
pyromellitic and naphthalene, adopts its favored overlap
arrangement. Pyromellitic diimides, in simple cocrystals and
within interlocked systems, have been found to favor solid-
state packing arrangements that place the long axes of the
diimide close to perpendicular with those of electron-rich
14
1
,15
1
,5-dioxynaphthalene derivatives. In the case of naphtha-
16
lene diimides, a nearly parallel arrangement is observed.
The solid-state structure of [2]catenane 13 reveals the
simultaneous satisfaction of these donor-acceptor structural
preferences, which also extend to the packing of individual
[2]catenanes in the crystal. In addition to a continuation of
alternating donor and acceptor subunits within the crystal
stacks, the perpendicular orientation of pyromellitic diimide
and naphthalene diether is maintained, as is the preference
for naphthalene diimides to be essentially parallel with this
electron-rich group. The overall structural preferences are
thus maintained both inter- and intramolecularly.
The work described in this Letter indicates that it could
be misleading to expect the deployment of donor-acceptor
interactions to be a sufficient primary design criterion for
new catenane syntheses. In isolation, such interactions do
not provide a sufficient driving force for successful molecu-
lar reaction. Only when the capacity to form C-H‚‚‚O
contacts is also present are successful assembly routes
Figure 3. Solid-state structure of [2]catenane 13.
1
7
uncovered.
being essentially coplanar with only small (1-2.5°) angles
between their mean planes. The naphthalene diether com-
ponents are rigorously planar, and the first O-methylene
bonds are only twisted from these planes by around 10°. In
Acknowledgment. We thank the U.K. EPSRC (J.K.M.S.)
and the ESF SMARTON project of the European Union
J.G.H.) for financial support of this work.
(
(
12) The shortest and strongest contacts (see ref 10) are those to the
central oxygen atom of the polyether chain: H‚‚‚O distance approximately
Supporting Information Available: Synthetic procedures
2
∠
(
.2 Å, C-H‚‚‚O ∠ 148°. All other contacts are around 2.7 Å and C-H‚‚‚O
and analytical data for 7 and 8 and macrocycles 4, 10, 12,
and [2]catenane 13; crystallographic data for [2]catenane 13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
100-120°. An additional, pertinent, example of a contact of this kind
H‚‚‚O distance approximately 2.9 Å, C-H‚‚‚O ∠ 128°) is to be found in
the structure of a phthalimido-crown, a system that contains both a polyether
chain and an imide-CH2 grouping, see: Ashton, P. R.; Huff, J.; Menzer,
S.; Parsons, I. W.; Preece, J. A.; Stoddart, J. F.; Tolley, M. S.; White, A.
J. P.; Williams, D. J. Chem. Eur. J. 1996, 2, 31-44.
OL991289W
(
13) We had previously attempted to prepare more soluble analogues of
[
2]catenane 3 by equipping the diimide precursor with solubilizing ethyl
groups in place of the methylene hydrogens, see: Hamilton, D. G.; Prodi,
L.; Feeder, N.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1 1999,
(14) Hamilton, D. G.; Montalti, M.; Prodi, L.; Fontani, M.; Zanello, P.;
Sanders, J. K. M. Chem. Eur. J. 2000, 6, 608-617.
1
057-1065. No interlocked products were obtained from these reactions,
and the product distribution from cyclizations of this modified diimide could
not be influenced in any way with electron-rich template molecules. We
attributed this failure to an inability of the soluble diimide to achieve a
favorable donor-acceptor overlap geometry with electron-rich substrates
as a result of the inclusion of bulky alkyl substituents. In light of the current
results this failure may have as much, or rather more, to do with the absence
of acidic methylene hydrogens occasioned by the inclusion of the additional
alkyl groups.
(15) Hamilton, D. G.; Lynch, D. E.; Byriel, K. A.; Kennard, C. H. L.
Aust. J. Chem. 1997, 50, 439-445.
(16) Lokey, R. S.; Iverson, B. L. Nature 1995, 375, 303-305.
(17) The capacity to form C-H‚‚‚O contacts is partly a consequence of
having “acidic” protons available, i.e. protons attached to electron-deficient
systems. Accordingly, and rather by default, successful systems are likely
to contain electron-deficient components (to provide the “acidic” protons)
and electron-rich donor sites such as oxygen atoms.
452
Org. Lett., Vol. 2, No. 4, 2000