Bis(hydroxy-isoindolinone)s: Synthesis, Stereochemistry, Polymer Chemistry, and Supramolecular Assembly

Article abstract of DOI:10.1021/ol101338m

Pseudoacid chlorides of 2,5-bis(4-fluorobenzoyl) terephthalic acid and 4,6-bis(4-fluorobenzoyl) isophthalic acid condense with primary amines to afford diastereomeric bis(hydroxyindolinone)s in good isolated yields and with diamines to give high molecular

Full text of DOI:10.1021/ol101338m

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3756-3759
Bis(hydroxy-isoindolinone)s: Synthesis,
Stereochemistry, Polymer Chemistry,
and Supramolecular Assembly
Howard M. Colquhoun,*,† Zhixue Zhu,*,† Christine J. Cardin,†
Andrew J. P. White,‡ Michael G. B. Drew,† and Yu Gan†
Department of Chemistry, UniVersity of Reading, Whiteknights, Reading RG6 6AD, U.K.,
and Department of Chemistry, Imperial College, South Kensington, London SW7 2AZ, U.K.
h.m.colquhoun@rdg.ac.uk; z.x.zhu@rdg.ac.uk
Received June 10, 2010
ABSTRACT
Pseudoacid chlorides of 2,5-bis(4-fluorobenzoyl) terephthalic acid and 4,6-bis(4-fluorobenzoyl) isophthalic acid condense with primary amines
to afford diastereomeric bis(hydroxyindolinone)s in good isolated yields and with diamines to give high molecular weight poly(hydroxyindolinone)s.
Bis-N-pyrenemethyl bis(hydroxyindolinone)s assemble, even in dipolar solvents such as DMSO, with macrocyclic diimide-sulfones to give
[3]pseudorotaxanes stabilized by electronically complementary aromatic π-π-stacking and shape-complementary van der Waals interactions.
Among the various noncovalent binding interactions, aro-
matic π-π-stacking has played a very significant role in the
development of supramolecular chemistry,1 with π-donor-π-
acceptor interactions being widely exploited for the construc-
tion of complex supramolecules2 and novel types of co-
crystals.3 For example, the development of π-electron-
accepting, tetracationic cyclophanes has enabled the synthesis
of entire families of charged catenanes, rotaxanes, redox-
driven switches, and molecular logic gates4 via templated
self-assembly with molecules containing π-electron-donor
(2) Early examples: (a) Colquhoun, H. M.; Stoddart, J. F.; Williams,
D. J.; Wolstenholme, J. B.; Zarzycki, R. Angew. Chem., Int. Ed. Engl. 1981,
20, 1051–1053. (b) Colquhoun, H. M.; Goodings, E. P.; Maud, J. M.;
Stoddart, J. F.; Williams, D. J.; Wolstenholme, J. B. J. Chem. Soc., Chem.
Commun. 1983, 114, 1140–1142.
† University of Reading.
‡ Imperial College.
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J. Chem. Soc., Perkin Trans. 2001, 2, 651–669. (b) Waters, M. L.
Biopolymers 2004, 76, 435–445. (c) Colquhoun, H. M.; Stoddart, J. F.;
Williams, D. J. Angew. Chem., Int. Ed. Engl. 1986, 25, 487. (d) Amabilino,
D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725–2828. (d) Stoddart, J. F.
Acc. Chem. Res. 2001, 34, 410–411.
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Chem. Soc. Jpn. 1966, 39, 547. (b) Williams, R. M.; Wallwork, S. C. Acta
Crystallogr. 1967, 23, 448. (c) Watt, S. W.; Dai, C.; Scott, A. J.; Burke,
J. M.; Thomas, R. Ll.; Collings, J. C.; Viney, C.; Clegg, W.; Marder, T. B.
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10.1021/ol101338m  2010 American Chemical Society
Published on Web 08/12/2010

aromatic units.5 A second important group of π-electron-
accepting macrocycles, based on aromatic diimides such as
naphthalene-tetracarboxylic diimide, has also afforded neutral
catenanes and rotaxanes by templated reactions of aromatic
diimides with 1,5-dialkoxynaphthalene derivatives.6
Prompted by the extreme thermochemical stability of
aromatic polyimides and polysulfones, we have recently
developed receptor molecules comprising macrocyclic ho-
mologues of such polymers.7 Macrocycles such as 1,
containing π-electron-accepting aromatic diimide residues
and biphenylene units with electron-withdrawing arenesulfo-
nyl substituents, are found to bind strongly to electron-rich
polycyclic arenes such as pyrene and perylene by electroni-
cally complementary π-π stacking.7 Computational model-
ing has also indicated that such binding might be reinforced
by O-H···OdC hydrogen bonding in complexes of 1,
through the introduction of hydroxylic substituents on the
guest molecule,7 and in this context we have now explored
the previously unknown N-pyrenemethyl hydroxy-isoindoli-
nones (e.g., 2) as potential components for assembly with
macrocyclic imide-sulfone receptors such as 1.
Figure 1. Macrocyclic receptor 1, guest compounds 2 and 2a, and
intermediate 3. Compounds 5 and 6 are key intermediates in the
present work, and 4 represents the only previous example of a
bis(hydroxy-isoindolinone).
Routes to hydroxy-isoindolinones generally involve either
addition of Grignard reagents to phthalimides or reactions
of pseudo-2-benzoyl benzoyl chlorides with primary amines.8
Here we chose to work with pseudo-2-(4-fluorobenzoyl)
benzoyl chloride (3) since the presence of the fluoro
substituent generates a characteristic set of multiplets in the
1H NMR spectrum which enables more straightforward
assignment of resonances. Thus, hydroxy-isoindolinone 2a
was obtained in 83% yield by condensation of 3 with
1-pyrenemethylamine in the presence of a tertiary amine.
Complexation of 2a with macrocycle 1 (1:2 molar ratio, 4
mM in 2a) in CDCl3/hexafluoropropan-2-ol (6:1, v/v) led to
large upfield shifts of the macrocycle resonances assigned
to Ha and Hb (0.68 and 0.97 ppm, respectively; see Figure
S3, Supporting Information), and a 1:1 binding constant of
8 × 102 M-1 ((10%)8 was determined for complex [1+2a]
in this solvent mixture.
Dipolar aprotic solvents such as DMF and DMSO gener-
ally inhibit molecular associations involving hydrogen bond-
ing and complementary π-π-stacking, through powerful
solvation of the interacting components.7,9 In this work,
however, significant binding between 2a and 1 (1:2 molar
ratio, 4 mM in 2a) was observed in DMSO, with the pink
color arising from intermolecular charge transfer still being
visually detectable and resonances assigned to Ha and Hb
still showing significant upfield shifts, ∆δ, of 0.19 and 0.31
ppm, respectively (Figure S4, Supporting Information).
Attempts to obtain single crystals for X-ray analysis of
the complex formed between 1 and 2a were unsuccessful,
but as centrosymmetric molecules often crystallize more
readily than noncentric structures, we next turned to analo-
gous bis(N-pyrenemethyl) bis(hydroxy-isoindolinone)s, as
potential components of supramolecular assemblies. Only a
single bis(hydroxy-isoindolinone) (4) has been reported previ-
ously, produced by condensation of ammonia with the pseudoac-
id chloride of 2-benzoyl benzoic acid.10 Interestingly, 4 was
originally formulated as 2,5-dibenzoyl terephthalamide,10a and
the actual bis(hydroxy-isoindolinone) structure was only recently
identified by single-crystal X-ray analysis.10b
In the present work, a mixture of the isomeric dicarboxylic
acids 5 and 6 was obtained by reaction of excess fluoroben-
zene with pyromellitic dianhydride in the presence of
aluminum chloride. Fractional crystallization gave pure 5 and
6 in 32% and 37% yields, respectively. Thionyl chloride
converted 5 and 6 to the pseudoacid chlorides 7 and 8,
respectively, and reactions of these pseudoacid chlorides with
pyrenemethylamine afforded the N-pyrenemethyl bis(hy-
droxy-isoindolinone)s 9 and 10 in 97% and 86% yields
(Scheme 1). The identities of compounds 7, 9, and 10 were
fully confirmed by spectroscopic and single-crystal X-ray
analyses (see Supporting Information).
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Org. Lett., Vol. 12, No. 17, 2010
3757

Scheme 1. Synthesis of Bis-N-pyrenemethyl
Hydroxy-isoindolinones 9 and 10
Both 9 and 10 are potentially diastereomeric, and although
the single crystals isolated in both cases were pure [R,S/S,R]
(anti) enantiomers, there is no obvious reason why the R,R/S,S
(syn) diastereomers should not also be formed. Indeed, the 1H
NMR spectrum of 9 showed two singlet hydroxyl resonances
and two triplet resonances arising from the protons ortho to
fluorine, in both cases with relative integrals of ca. 5.5:1 (Figures
S5 and S6, Supporting Information). Analogous pairs of
resonances were also observed in the spectrum of 10, though
with relative integrals of ca. 3.0:1 reflecting the presence of
diastereomers in the same molar ratio.
Figure 2. X-ray structure of the [3]pseudorotaxane 11, formed by
assembly of macrocycle 1 (two molecules, in blue) with compound
9 (1 molecule, anti isomer). The shape complementarity of the
assembled components is evident in the matching of van der Waals
surfaces. The hydroxylic hydrogens of 9 do not interact with the
macrocycle in the crystal but may form hydrogen bonds to
disordered DMSO.
Complexation of pale yellow macrocycle 1 with colorless
9 in chloroform/hexafluoropropan-2-ol (6:1 v/v) produced
an intense red color, indicating formation of a π-π-stacked
complex, and 1H NMR studies in this same solvent showed
upfield shifts for the macrocycle resonances assigned to Ha
and Hb (Figure 1) of 0.87 and 1.00 ppm, respectively, at a
1:1 mol ratio of the two components (Figure S7, Supporting
Information). As with 2a, complexation of 9 with macrocycle
1 was noticeably weaker in DMSO than in chloroform/
hexafluoropropan-2-ol as judged by 1H NMR complexation
shifts (Figure S9, Supporting Information). Nevertheless,
deep red single crystals suitable for X-ray analysis were
obtained by vapor diffusion of methanol into a solution of 1
and 9 (2:1 molar ratio) in DMSO. The crystal structure
confirmed formation of a centrosymmetric [3]pseudorotaxane
(11), with each pyrene unit of 9 being fully encapsulated by
a molecule of 1 (Figure 2).
nylene unit and diimide ring system are 3.81 and 3.68 Å,
respectively. The diameter of macrocycle 1 (from the centroid
of the biphenylene linkage to the centroid of the diimide
residue) contracts from 8.19 Å, in its unbound state,7 to 7.40
Å on binding to compound 9. There are close contacts between
the fluorophenyl ring of 9 and the 4-sulfonylphenoxy ring of
1, in the form of shape-complementary C-H···π and a range
of other van der Waals interactions (see Figures 2 and S14,
Supporting Information). In view of the unexpected absence
of hydrogen bonding between components 1 and 9, we conclude
that it is these shape-complementary interactions which provide
the additional stabilization needed for assembly of the [3]pseu-
dorotaxane in dipolar solvents such as DMSO.
The pseudoacid chlorides 7 and 8 also react cleanly with
primary aromatic amines, specifically 1,4-toluidine, affording
compound 12 in 68% isolated yield (Scheme 2). The X-ray
structure of the anti diastereomer of 12 is shown in Figure
3, again confirming that hydroxy-isoindolinones (not amides)
are formed in this type of reaction. This result strongly
The principal contribution to binding clearly arises from
multiple donor-acceptor π-π-stacking between the electron-
rich pyrene and electron-deficient diimide and biphenylene-
disulfone units. The transannular distances between the
centroid of the pyrene unit and the centroids of the biphe-
(10) (a) Liu, S.; Jiang, P.; Song, G. L.; Liu, R.; Zhu, H. J. Dyes Pigments
2009, 81, 218. (b) Liu, S.; Liu, J. N.; Jiang, P.; Chu, Q. Y.; Zhu, H. J. Acta
Crystallogr. 2008, E64, o2479.
3758
Org. Lett., Vol. 12, No. 17, 2010

Scheme 2. Synthesis of the Di-p-tolyl
Bis(hydroxy-isoindolinone) 12 and the Analogous Polymer 13
Figure 3. X-ray structure of the bis(hydroxy-indolinone) 12 (anti-
isomer). The molecule has a crystallographic center of symmetry,
and each hydroxy group forms a strong hydrogen bond (OH···OdC
) 1.89 Å, O···H···O ) 173°) to a molecule of solvating dimeth-
ylformamide.
ously been reported to yield conventional polyamides,11 but in
view of the results described here, it seems almost certain that
these “polyamides” must be poly(hydroxy-isoindolinone)s,
analogous to 13.
suggested that high molecular weight poly(hydroxy-isoin-
dolinone)s might be accessible by condensation of 7 and 8
with aromatic diamines, and indeed condensation of 7 with
1,4-phenylenediamine (1:1 mol ratio, Scheme 2) in N-
methylpyrrolidone (NMP) afforded polymer 13 in 98% yield,
with an inherent viscosity (in NMP) of 0.70 dL g-1.
Acknowledgment. This work was supported by EPSRC
under Grants EP/C533526/1, EP/C533526/1, and EP/E00413X/
1. Spectroscopic and crystallographic work was carried out
in the University of Reading Chemical Analysis Facility
(CAF) and at Imperial College, London.
Gel permeation chromatography (GPC) of 13 gave values
of Mn ) 78 kDa and Mw ) 95 kDa, relative to polystyrene
standards, confirming the formation of high molecular weight
Supporting Information Available: Methods and materi-
als. Detailed experimental procedures and full characteriza-
tion data for 2a, 5, 6, 7, 8, 9, 10, 12, and 13. Crystal data
and full crystallographic information for 7, 9, 10, 11, and
12 (CCDC 780120, 780121, 761447, 780122, and 780123,
respectively) in CIF format. Proton NMR spectra of mac-
rocycle 1 showing complexation with 2a, 9, and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
polymeric material, and H NMR datasthough broadened
considerablyswere consistent with the proposed structure
(Scheme 2). This new type of polymer, containing a rigid
aromatic backbone and a high density of hydrophilic hy-
droxyl groups on the main chain, could have potential
applications in areas such as nonfouling and highly functional
materials for pharmaceutical or biomedical applications. In
passing, it should be noted that reactions of the pseudoacid
chlorides of 2,5-dibenzoyl terephthalic acid and 4,6-dibenzoyl
isphthalic acid with aliphatic primary diamines have previ-
OL101338M
(11) Ueda, M.; Ohkura, M.; Imai, Y. J. Polym. Sci., Polym. Chem. Ed.
1974, 12, 719–727.
Org. Lett., Vol. 12, No. 17, 2010
3759