Cyclobisintercaland Macrocycles: Synthesis and Physicochemical Properties of Macrocyclic Polyamines Containing Two Crescent-Shaped Dibenzophenanthroline Subunits

Article abstract of DOI:10.1021/jo970496b

A general access to isomeric dibenzo[b,j]phenanthrolinedicarboxaldehydes is described. These pentacyclic planar quinacridine compounds exhibit crescent-shaped forms that fulfill the geometrical requirements of providing broad overlap of nucleobase pairs o

Full text of DOI:10.1021/jo970496b

5458
J . Org. Chem. 1997, 62, 5458-5470
Cyclobisin ter ca la n d Ma cr ocycles: Syn th esis a n d P h ysicoch em ica l
P r op er ties of Ma cr ocyclic P olya m in es Con ta in in g Tw o
Cr escen t-Sh a p ed Diben zop h en a n th r olin e Su bu n its
Olivier Baudoin, Marie-Paule Teulade-Fichou, J ean-Pierre Vigneron, and J ean-Marie Lehn*
Laboratoire de Chimie des Interactions Mole´culaires (CNRS, UPR 285), Colle`ge de France,
11 place M. Berthelot, 75005 Paris, France
Received March 18, 1997X
A general access to isomeric dibenzo[b,j]phenanthrolinedicarboxaldehydes is described. These
pentacyclic planar quinacridine compounds exhibit crescent-shaped forms that fulfill the geometrical
requirements of providing broad overlap of nucleobase pairs or triplets. The dialdehyde derivatives
have been condensed with various polyamines to give macrocyclic dimeric structures, cyclobisin-
tercalands, of variable size, charge, and shape. The related water-soluble monomeric quinacridines
were prepared from the dialdehydes by grafting ammonium groups. The physicochemical properties
of the monomeric quinacridines and of the macrocyclic bis-quinacridines have been investigated
by spectroscopic methods (UV-vis, fluorescence, NMR). The results show that some of these
macrocyclic compounds could exist as semiclosed conformers suitable to accommodate a pair of
nucleotides.
In tr od u ction
admitted to appreciably enhance the attraction between
π-systems in aqueous medium. This effect, which is more
likely to be due to increased solvophobic effects, has been
frequently documented by experiments based on simple
chemical modifications.5
Noncovalent interactions between aromatic systems
contribute significantly to the stabilization of secondary
and tertiary structures of biological macromolecules and
thus play a crucial role in many physiological processes
both on a structural and functional point of view. Inter
alia the aromatic stacking is one of the basis components
of the canonical B-helix structure of the DNA along with
the Watson-Crick base pairing.1 This interaction is also
directly involved in the anchoring of DNA duplexes by
many natural cytostatic agents such as antibiotics and
antitumor drugs and by numerous synthetic DNA bind-
ers.2 All these compounds display a common structural
feature, i.e., coplanar hydrophobic moieties able to over-
lap with the heterocyclic nucleobases. Their binding to
the targeted helical DNA segment may lead to serious
local distortions from the normal geometry; one of the
most striking example is the binding of quinoxaline
antibiotics which induces Hoogsteen base pairing instead
of the Watson-Crick hydrogen bonding.2a Interestingly
π-stacking appears to govern both the stability of the
double-helix structure and its conformational variability.
Despite the large number of studies aimed at clarifying
the exact nature of the interaction between aromatic
groups, there is still much debate on this subject.3,4
However, some electronic and structural effects of inter-
est for molecular design are well established. Among
them, extension of the aromatic surface area is commonly
In the context of supramolecular chemistry and mo-
lecular recognition studies, this structural effect has been
widely applied for the design of artificial receptors able
to bind a variety of substrates, in particular nucleotides.6
To this end, in the course of our studies on anion
recognition, we developed the cyclobisintercaland type of
receptors7 (built on two intercalative units linked by
polyammonium chains), tailored to trap aromatic sub-
strates bearing anionic groups by the simultaneous
interplay between electrostatic attraction and “sandwich-
ing” of the guest by π-stacking. Indeed the members of
the series possessing naphthalene and acridine units
bridged by diethylenetriamine moieties displayed re-
markably high affinities for nucleotides in water (106 M-1
< Kassoc < 108 M-1).7b,c Moreover considerable enhance-
ments of the stability of the complexes have been
observed when the size of the intercalative unit was
increased, pointing to the importance of the π-stacking
interaction in the binding.7c Furthermore a major at-
(4) (a) Guckian, K. M.; Schweitzer, B. A ; Ren, R. X.-F.; Sheils, C.
J .; Paris, P. L.; Tahmassebi, D.; Kool, E. T. J . Am. Chem. Soc. 1996,
118, 8182 and references cited therein. (b) Ren, X.-F.; Schweitzer, B.
A.; Sheils, C. J .; Kool, E. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
743.
(5) (a) Rebek, J ., J r. Angew. Chem., Int. Ed. Engl. 1990, 29, 245. (b)
Lin, K.-Y.; J ones R. J .; Matteucci, M. J . Am. Chem. Soc. 1995, 117,
3873 and references cited therein.
(6) (a) Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71. (b)
Hamilton, A. Adv. Supramol. Chem. 1991, 1, 1. (c) Hosseini, M. W.;
Blacker, A. J .; Lehn, J .-M. J . Am. Chem. Soc. 1990, 112, 3896. (d)
Galan, A.; Pueyo, E.; Salmeron, A.; de Mendoza, J . Tetrahedron Lett.
1991, 32, 1827. (e) Schneider, H. J .; Blatter, T.; Palm, B.; Pfinstag,
U.; Ru¨diger, V.; Theis, I. J . Am. Chem. Soc. 1992, 114, 7704. (f) Rotello,
V. M.; Viani, E. A.; Deslongchamps, G.; Murray, B. A.; Rebek, J ., J r.
J . Am. Chem. Soc. 1993, 115, 797. (g) Shionoya, M.; Ikeda, T.; Kimura,
E.; Shiro, M. J . Am. Chem. Soc. 1994, 116, 3848.
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
(1) Saenger, W. Principles of nucleic acid structures; Springer-
Verlag: New York, 1984; pp 132-133.
(2) (a) Quigley, G. J .; Ughetto, G.; Van Der Marel, G. A.; Van Boom,
J . H.; Wang, A. H.-J .; Rich, A. Science 1986, 232, 1255. (b) Kennard,
O.; Hunter, W. N. Angew. Chem., Int. Ed .Engl. 1991, 30, 1254. (c)
Brown, D. R.; Kurz, M.; Kerans, D. R.; Hsu, V. L. Biochemistry 1994,
33, 651. (d) Pindur, U.; Haber, M.; Sattler, K. J . Chem. Educ. 1993,
70, 263. (e) Wilson, D. W.; Ratmeyer, L.; Zhao, M.; Strekowski, L.;
Boykin D. Biochemistry 1993, 32, 4098.
(3) (a) Sanders, J . M.; Hunter, C. A. J . Am. Chem. Soc. 1990, 112,
5525. (b) Hunter, C. A Angew. Chem., Int. Ed. Engl. 1993, 32, 1584.
(c) Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, J . S. J .
Am. Chem. Soc. 1992, 114, 5729. (d) Cozzi, F.; Cinquini, M.; Annun-
ziata, R.; Siegel J . S. J . Am. Chem. Soc. 1993, 115, 5330. (e) Cozzi, F.;
Ponzini, F.; Annunziata, R.; Cinquini, M.; Siegel J . S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1019.
(7) (a) Claude, S.; Lehn, J .-M.; Schmidt, F.; Vigneron, J .-P. J . Chem.
Soc., Chem. Commun. 1991, 1182. (b) Dhaenens M.; Lehn J .-M.;
Vigneron J .-P. J . Chem. Soc., Perkin Trans.
2 1993, 1379 and
references cited therein. (c) Teulade-Fichou M.-P.; Vigneron, J .-P.;
Lehn, J .-M. Supramol. Chem. 1995, 5, 139. (d) Cudic, P.; Zinic, M.;
Tomisic, V.; Simeon, Vl.; Vigneron, J .-P.; Lehn, J .-M. J . Chem. Soc.,
Chem. Commun. 1995, 1073.
S0022-3263(97)00496-9 CCC: $14.00 © 1997 American Chemical Society

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5459
tractive property of these receptors is their pronounced
solubility in water near the physiological pH (up to 10-2
M at pH 6-7), by contrast with most macrocyclic aro-
matic systems which frequently exhibit poor solubility
in aqueous media.
Up to now, most of the molecular receptors have been
built to trap a single nucleotide (1/1 complexes), but the
recognition of nucleobase pairs by systems able to bind
two nucleotides through the formation of 2/1 stoichio-
metric associations has not been achieved, despite its
fundamental and applied interest. However, several
model compounds bearing a nucleobase in their frame-
work perform the recognition of the complementary base8
and more recently a new conceptual approach which rests
on the insertion of a molecular wedge between two
nucleobases (matched or not) by formation of two hydro-
gen-bonding arrays has been proposed.9 In addition to
the dominant Watson-Crick type pairing mode, a num-
ber of base associations involving other hydrogen-bonding
patterns (Hoogsteen, reverse Hoogsteen, homo-base pair-
ing)10 also play a significant role in the formation of
ordered oligonucleotide structures such as duplexes,11a-c
triplexes,11d,e and tetraplexes.11f-h Due to their biological
relevance, the structural and functional aspects of these
pairings are the focus of intensive investigations, further
stimulated by potential therapeutic applications.11-13
F igu r e 1. (A) Overlap of G-C base pair held in the Watson-
Crick mode by a planar crescent-shaped pentacyclic unit; (B)
overlap of a T-A×T base triplet held in the Watson-Crick ×
Hoogsteen mode by a planar crescent-shaped pentacyclic unit.
Hoogsteen duplex.15b These effects arise in part from
enhanced hydrophobic effects and aromatic stacking
interactions.
Among the fused aromatic compounds, and in ac-
cordance with the geometric requirements shown in
Figure 1, the dibenzo[b,j]phenanthrolines, i.e., quina-
cridines17 appeared to be good candidates. We report
here the preparation of a series of these heterocyclic
compounds through a versatile and general procedure
and their use as monomeric synthons for building cyclo-
bisintercaland-type receptors of large size. The physi-
cochemical properties of the monomeric dibenzophenan-
throlines and of the corresponding dimeric macrocycles
have been investigated by spectroscopic methods (RMN,
UV-vis absorption, and fluorescence spectroscopies). The
comparative analysis of the results suggests that these
macrocyclic molecules could provide suitable hydrophobic
microenvironments for the complexation of pairs of
nucleotides.
Our approach to the binding of a base pair rests on
the search for molecular units exhibiting extended aro-
matic surface areas able to stabilize canonical and
nonusual nucleobase associations through increased
π-interactions. Simple geometric considerations and
literature examination10-16 led us to design an angular
pentacyclic molecular pattern which possesses a suitable
shape and size for overlapping with either Watson-Crick
or Hoogsteen matched base pairs, or base triplets (Figure
1). Recently planar aromatic compounds that adopt the
crescent-shaped geometry, such as coralyne14 and benzo-
[e]pyridoindole derivatives (BePIs),15 have been shown
to induce significant stabilization of triple helices as well
as reorganization of a Watson-Crick duplex into a
(8) (a) Constant, J . F.; Fahy, J .; Lhomme, J . Tetrahedron Lett. 1987,
16, 1777. (b) Furuta, H.; Magda, D.; Sessler, J . L. J . Am. Chem. Soc.
1991, 113, 978. (c) Schall, O. F.; Gokel, G. W. J . Am. Chem. Soc. 1994,
116, 6089. (d) Gokel G. W.; Schall, O. F. J . Org. Chem. 1996, 61, 1449.
(9) Branda, N.; Kurz, G.; Lehn, J .-M. J . Chem. Soc., Chem. Commun.
1996, 2443.
(10) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer-Verlag: New York, 1991; p 247.
(11) (a) Edwards, E. L.; Ratliff, P. R. L.; Gray, D. M. Biochemistry
1990, 29, 1417. (b) Holbrook, S. R.; Cheong, C.; Tinoco, I.; Kim, S.-H.
Nature 1991, 353, 579. (c) Nikonowicz, E. P.; Gorenstein, D. G.
Biochemistry 1990, 29, 8845. (d) Felsenfeld, G.; Miles, H. T. Annu. Rev.
Biochem. 1967, 36, 407. (e) Htun, H.; Dahlberg J . E. Science 1989,
243, 1571. (f) Sen, D.; Gilbert, W. Nature 1988, 334, 364. (g) Sundquist,
W. I.; Klug, A. Nature 1989, 342, 825. (h) Gehring K.; Leroy, J .-L.;
Gue´ron, M. Nature 1993, 363, 561.
Syn th esis
The quinacridines are the parent aromatic compounds
of the quinacridones,18 which received attention 30 years
ago owing to their remarkable crystalline polymorphism
and dyestuff properties, while more recently their use as
organic semiconductors has renewed the interest.18c
However there are only very few examples in the
literature of those fully aromatic planar pentacyclic
systems that can exist in linear or angular form.19 The
most recent approach to some angular quinacridines was
proposed in 198519f but is limited to the introduction of
substituents at the para positions to the nitrogen atoms
(see Chart 1).
(12) (a) Le Doan, T.; He´le`ne, C. Nucleic Acids Res. 1987, 15, 7749.
(b) Moser, H. E.; Dervan, P. B. Science 1987, 238, 645. (c) Strobel, S.
A.; Dervan, P. B. Science 1990, 249, 73. (d) Thuong, N. T.; He´le`ne, C.
Angew. Chem., Int. Ed. Engl. 1993, 32, 666. (e) He´le`ne, C. Antisense
Research and applications; Cooke, S. T., Lebleu, B., Eds.; CRC Press,
Boca Ratan, FL, 1993; p 375.
(13) Le, S.-Y.; Pattabiraman, N.; Maizel, J . V., J r. Nucleic Acids Res.
1994, 22, 3966.
(14) Lee, J . S.; Latimer, L. J . P.; Hampel, K. J . Biochemistry 1993,
32, 5591.
(15) (a) Escude´, C.; Nguyen, C. H.; Mergny, J . L.; Sun, J .-S.; Bisagni,
E.; Garestier, T.; He´le`ne, C. J . Am. Chem. Soc. 1995, 117, 10212. (b)
Escude´, C.; Mohammadi, S.; Sun, J .-S; Nguyen, C. H.; Bisagni, E.;
Liquier, J .; Taillandier E.; Garestier, T.; He´le`ne, C. Chem. Biol. 1996,
3, 57.
(16) (a) Haq, I.; Ladbury, J . E.; Chowdhry, B. Z.; J enkins, T. E. J .
Am. Chem. Soc. 1996, 118, 10693. (b) Fox, K. R.; Polucci, P.; J enkins,
T. C.; Neidle, S. Proc Natl. Acad. Sci. U.S.A. 1995, 92, 7887.
(17) Acheson, R. M. Acridines, The Chemistry of Heterocyclic Com-
pounds; J ohn Wiley & Sons, Interscience: 1973; Vol. 9, p 563.
(18) (a) Labana, S. S.; Labana, L. L. Chem. Rev. 1967, 67, 1. (b)
Potts, G. D.; J ones, W.; Bullock, J . F.; Andrews, S. J .; Maginn, S. J . J .
Chem. Soc., Chem. Commun. 1994, 2565. (c) Manabe, K.; Kusabayashi,
S; Yokoyama, M. Chem. Lett. 1987, 609.
(19) (a) Niementowski, S. Chem. Ber. 1906, 39, 385. (b) Ullmann,
F.; Maag, R. Chem. Ber. 1907, 40, 2515. (c) Badger G. M.; Pettit R. J .
Chem. Soc. 1952, 1874. (d) Dali, H. M.; Gogte V. N.; Mullick, G. B.;
Tilak, B. D. Indian J . Chem. 1974, 12, 1230. (e) Belser, P.; Zelewsky,
V. A. Helv. Chim. Acta 1980, 63, 1675. (f) Hellwinkel, D.; Ittemann,
P. Liebigs Ann. Chem. 1985, 1501.

5460 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
Ch a r t 1a
Sch em e 1
a
Nomenclature and numbering system for [x,y]-phenanthroline
and dibenzo[b,j][x,y]phenanthroline rings (according to CAS, the
phenanthroline nomenclature is used for the position of the two
ring N in the dibenzophenanthroline skeleton).
tions such as variation of the solvent or activation of the
copper catalyst22 failed to improve the yield of the double
condensation. The possibility of reacting the three (ortho,
meta, para) isomers of diodobenzene is at the basis of
the versatility of the method that allows the construction
of a family of dibenzo[b,j]phenanthrolines with [1,10],
[1,7] and [4,7] patterns.19f
In our previous work on cyclobisintercaland receptors,7
symmetrical aromatic dialdehydes have proven to be
suitable intermediates for the preparation of both water
soluble monomers by grafting hydrophilic polyammonium
chains and dimeric macrocyclic systems through conden-
sation with a diamine. These key compounds are gener-
ated by direct oxidation of the dimethyl precursors. In
the case of quinacridines the prerequisite dimethyl
derivatives bearing the methyl groups on the external
benzo rings were not accessible by the existing methods.
Therefore a methodology has been developed that offers
the possibility of introducing methyl substituents at
suitable positions but also of varying the relative places
of the two ring nitrogens.
P r ep a r a tion of Qu in a cr id in ed ica r boxa ld eh yd es.
The quinacridines may be considered as condensed
acridines or as dibenzophenanthrolines, and thus the
synthetic routes to these structures are related to both
acridine and phenanthroline chemistry. A particularly
attractive approach would involve the Friedla¨nder con-
densation20 of cyclohexanediones with o-aminobenzalde-
hydes. Unfortunately, reacting 2-amino-5-methylben-
zaldehyde with 1,2-cyclohexanedione provided the desired
6,7-dihydrodibenzophenanthroline in poor yield, likely
due to self-condensation of the starting aminoaldehyde;
furthermore this intermediate appeared particularly
resistant to oxidation by classical reagents.21
Two different synthetic pathways had to be used to
obtain the three isomeric dimethylquinacridines 5a -c
(Schemes 2 and 3) due to the particular behavior of the
ortho-condensed product (3a ) compared to the para and
meta isomers (3b,c). Treatment of compounds 3b and
3c with phosphorus oxychloride (POCl3)17 provided dichlo-
roquinacridines 4b,c (Scheme 2) in moderate yields as
compared to those observed with single acridine deriva-
tives.7c In principle the cyclization could lead to an
angular or a linear structure, but no trace of the latter
was detected in both cases. The mechanism of the ring
closure proceeds through the formation of a mixed
anhydride followed by intramolecular acylation and
elimination of hydrochloric acid.17 The exclusive forma-
tion of an angular structure could be explained by the
intervention of the half-closed intermediate depicted in
Scheme 4: in this hypothetical intermediate, double
bonds would lie in fixed positions so that the only
orientation for the second cyclization would be toward
the angular form. A similar rationale can be applied to
the meta isomer. The predominant formation of the
angular isomer (>95%) has also been observed in the
preparation of p-quinacridones.18,19c
These unsuccessful attempts prompted us to devise
another strategy transposed from the synthesis of sub-
stituted acridine rings.7c It is based on the double
condensation of diiodobenzene derivatives 2 with 5-meth-
ylanthranilic acid (1) (Ullmann-Goldberg condensation)
(Scheme 1). Mixtures of mono- and disubstituted prod-
ucts were systematically obtained, but the compounds
were easily separated by precipitation in hydroalcoholic
media. However mention should be made of the require-
ment for iodo derivatives to reach acceptable yields (40-
60%) of the disubstituted compounds, especially in the
less reactive ortho series where the use of 1,2-dibro-
mobenzene leads to the exclusive formation of the mono-
condensed product. Modifications of the reaction condi-
Several attempts to induce the closure of o-dianthra-
nilic acid 3a by phosphorus oxychloride gave dark and
complex mixtures. This led us to apply another cycliza-
tion method using concentrated sulfuric acid that con-
verted 3a to quinacridone (4a ) (Scheme 3). Subsequent
reduction by LiAlH4 respectively (4b,c Scheme 3) or Na
in refluxing pentanol (4a , Scheme 4) afforded in the three
cases a mixture containing the dimethylquinacridine 5
along with hydrogenated derivatives. The fully aroma-
tized compounds 5 were finally obtained in pure form by
reoxidation under mild conditions (FeCl3). Oxidation of
the dimethyl intermediates 5 to the dialdehydes 6 was
carried out in hot naphthalene with controlled amounts
(22) (a) Rieke, R. D.; Rhyne, D. L. J . Org. Chem. 1979, 44, 3445. (b)
Gauthier S.; Fre´chet, J . M. J . Synthesis 1987, 383. (c) Carrasco, R.;
Pellon, R. F., Elguero, J .; Goya, P.; Pae`z, J . A. Synth. Comm. 1989,
11&12, 2077. (d) Pellon, R. F.; Carrasco, R.; Rodes, L. Synth. Commun.
1993, 23, 1447.
(20) (a) Thummel, R. P. Synlett 1992, 1, 1. (b) Hung, C.-Y.; Wang,
T.-L.; Shi, Z.; Thummel, R. P. Tetrahedron 1994, 50, 10685.
(21) For a review, see: Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 4,
317.

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5461
Sch em e 2
Sch em e 3
Sch em e 4. P r op osed In ter m ed ia te for th e
F or m a tion of Cr escen t-Sh a p ed P olycycles
of selenium dioxide; the use of naphthalene as solvent
has been mentioned in an earlier report7c and afforded a
considerable improvement in the oxidation of aromatic
methyls as the reaction did not proceed at all in the usual
solvents such as dioxane.23
the terephthalate dianion.24 Furthermore the pKa values
of the three amino groups of diethylenetriamine (3.5, 8.0,
9.0) are compatible with the presence of a unique or
largely predominant tetracationic form of the receptor
at pH 6. Thus, condensation of 6a and 6b respectively
with diethylenetriamine afforded after reduction with
NaBH4 the macrocycles 7a and 7b in reasonable yields
(Scheme 5). Protonation by aqueous HCl gave the water-
soluble forms 7a ,HCl and 7b,HCl which are schemati-
cally represented by their tetraprotonated forms pre-
dominant at pH 6 (Figure 2).
P r ep a r a tion of Ma cr ocyclic Bisqu in a cr id in es.
The macrocyclic structures were readily obtained via the
efficient 2 + 2 condensation between dialdehydes and
diamines. Indeed, and despite the low solubility of the
aromatic dialdehydes used in earlier work,7 macrocy-
clization generally occurred in good yields under moder-
ate dilution conditions ([dialdehyde] ) 10-3 M). In the
present case only compounds 6a and 6b appeared suit-
able to be engaged in cyclization experiments for sym-
metry reasons: the reaction proceeds unambiguously
with dialdehydes 6a and 6b both of C2v symmetry; on
the contrary the unsymmetrical dialdehyde 6c offers two
modes for cyclization which would give mixtures of
isomeric macrocycles.
1. Con d en sa tion w ith Dieth ylen etr ia m in e. Using
diethylenetriamine groups as bridging moieties allows
the building of cyclobisintercalands of suitable size and
flexibility to accommodate aromatic substrates. Indeed
evidence that such receptors might adopt a semiclosed
conformation with aromatic units in parallel plans creat-
ing a cavity where the anionic aromatic guest is inserted
has been recently provided by X-rays analysis of a
complex between a bisnaphthalene cyclointercaland and
2. Use of Oth er P olya m in es. To investigate the
versatility of the method and to obtain analoguous
macrocycles of larger size, different overall charge, and
conformation, various polyamines were reacted with
dialdehyde 6a . The oxygenated analogue of diethylen-
etriamine, [2,2′-oxybis(ethylamine)], provided macrocycle
8 which displays physicochemical properties very similar
to those of 7a (Scheme 5). Attempts to use longer
polyamines met with some difficulties. Indeed complex
mixtures of products were generated upon reaction of 6a
with dipropylenetriamine whereas cyclization with its
analogue methylated on the central nitrogen atom pro-
(23) Chandler, C. J .; Deady, L. W.; Reiss, J . A. J . Heterocycl. Chem.
1981, 18, 599.
(24) Cesario, M.; Paris, T.; Vigneron, J .-P.; Lehn, J .-M. J . Inclusion.
Phenom. Mol. Recognit. Chem., in press.

5462 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
Sch em e 5
duced macrocycle 9 in reasonable yield and purity. This
dramatic difference in reactivity between the two poly-
amines might be interpreted in terms of formation of
cyclic aminals that prevents macrocyclization from oc-
curring normally (Scheme 6), the N-methylated system
deprived from the hydrogen atom on the central amine
being unable to produce such intermediates. The forma-
tion of aminal derivatives was demonstrated by reacting
6a with propylenediamine which gave the corresponding
6-membered ring diaminal (10, Scheme 6) that was
characterized by 1H NMR. Such isomeric forms of
macrocyclic tetraimines have been described25 and seem
to occur also with ethylene or propylenepolyamines
according to a 5(or 6)-endo-trig attack.26 However these
examples are related to macrocyclic systems of small size
containing subunits such as benzene or pyridine. In our
case the formation of 5-membered ring aminals with
diethylenetriamine has never been observed and might
be disfavored by the steric hindrance of the large aro-
matic moieties. On the other hand, the formation of
aminals from propylenepolyamines which might be fa-
vored by the higher flexibility of the chains and the
stability of the 6-membered ring hinders the macrocy-
clization step.
P r ep a r a tion of Wa ter -Solu ble Mon om er ic Qu in a -
cr id in es. As mentioned in the introduction, derivatives
of the parent quinacridine unit are of much interest in
investigating the π-stacking effect with various biological
targets. Furthermore they are also required as models
to interpret properly the spectroscopic properties of the
dimeric macrocyclic assemblies. So far, monomeric quina-
cridinediimines have been synthesized by using a large
excess of n-propylamine (or N,N-dimethylpropylenedi-
amine) for condensation to dialdehydes 6 (Scheme 7) and
then have been converted to the corresponding proto-
nated quinacridines (11,HCl) and (12,HCl) by the usual
procedure. Such compounds constituted of one mono-
meric unit bearing positive charges mimick half a mac-
rocycle. Furthermore the structural variations exhibited
from one series to another could strongly influence
intrinsic properties of the aromatic nucleus such as
polarizability and electronic density repartition and
might have fundamental consequences on their stabiliz-
ing effect toward double- or triple-helix structures as has
been demonstrated recently.16b
Sp ectr oscop ic a n d P h ysicoch em ica l P r op er ties
of Mon om er ic Qu in a cr id in es a n d Ma cr ocyclic Bis-
qu in a cr id in es. 1. Dim eth ylqu in a cr id in es: An gu -
la r ver su s Lin ea r Str u ctu r e. The structure of 5a is
obviously angular according to its synthetic pathway
whereas the bent form of the monomeric quinacridines
5b,c is supported by NMR and UV-vis spectroscopic
analysis. Considering that the absorption spectra of
aromatic heterocyclic compounds closely resemble those
(25) (a) Adams, H.; Bailey, N. A.; Fenton, D. E.; Good, R. J .; Moody,
R.; Rodriguez de Barbarin, C. O. J . Chem. Soc., Dalton Trans. 1987,
207. (b) Adams, H.; Bailey, N. A.; Fenton, D. E.; Hempstead, P. D.;
Westwood, G. P. J . Inclusion. Phenom. Mol. Recognit. Chem. 1991, 11,
63. (c) Rockcliffe, D. A.; Martell, A. E.; Reibenspies, J . H. J . Chem.
Soc., Dalton Trans. 1996, 167. (d) Adams, H.; Bailey, N. A.; Bertrand,
P.; Collinson, S. R.; Fenton, D. E.; Kitchen, S. J . J . Chem. Soc., Dalton
Trans. 1996, 1181.
F igu r e 2. Schematic representation of macrocycles 7a and
7b in their tetraprotonated forms at pH 6.
(26) Baldwin J . E., J . Chem. Soc., Chem. Commun. 1976, 734.

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5463
Sch em e 6. P r op osed F or m a tion of 6-Mem ber ed Rin g Am in a ls
Sch em e 7
of their carbocyclic analogues, a linear quinacridine
Finally in the case of 5c, the observation of two distinct
peaks (8.29 and 9.79 ppm) for the protons para to the
heteroatoms (H8 and H14) are in agreement with an
unsymmetrical molecule corresponding to a bent aro-
matic skeleton (H8 and H14 would indeed be equivalent
in the linear form of C2v symmetry). Therefore these data
demonstrate unambiguously the angular structure of
quinacridines 5b and 5c.
2. Deter m in a tion of th e p Ka ’s of Mon om er ic
Com p ou n d s 11. Knowledge of the pKa’s of the nitrogen
sites of the water-soluble monomeric quinacridines is
necessary in order to gain information about the proton
distribution at different pH and also to compare it with
that of the macrocyclic dimers. To this end we studied
the absorption and fluorescence properties of compounds
11 in aqueous solution at various pH.
should be strongly colored like pentacene, a linearly fused
pentacyclic molecule which displays a deep blue color.19c
On the contrary, compounds 5b and 5c both exhibit a
pale yellow color, their absorption spectra presenting
three main bands in the near-UV region with peaks at
314, 332, and 361 nm (5b) and 315, 329, and 350 nm (5c),
similar to that of 5a (314, 326, and 351 nm).
1
The H NMR spectrum of 5b shows that the H13 and
H14 protons in the para positions to the nitrogen atoms
are equivalent, giving a resonance at 9.35 ppm; this does
not allow one to discriminate between the linear or the
angular structure of 5b since the molecules are sym-
metrical in both cases. However the large downfield shift
of the signal indicates a strong interaction between H13
and H14 that can only arise from the angular form.

5464 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
F igu r e 3. Absorption and (inset) fluorescence spectra (λexc
)
324 nm) of 11a 1.0 × 10-5 M in water (10 mM NaCl) with
gradual enhancement of pH from 1.2 to 5.0.
F igu r e 5. Absorption and (inset) fluorescence spectra (λexc
)
327 nm) of 11b 1.0 × 10-5 M in water (10 mM NaCl) with
gradual enhancement of pH: (A) from 1.2 to 2.4; (B) from 2.4
to 5.0.
F igu r e 4. Normalized changes in absorbance of 11a at 382
([) and 320 (0) nm and in fluorescence intensity at 437 nm
(2) as a function of pH.
sponding to the deprotonation of a nitrogen atom of the
quinacridine ring. There is no evidence for another
protonation process in the pH range examined, in agree-
ment with the low pKa value of the first N atom in the
1,10-phenanthroline (pKa ) -1.4 ).27e The meta isomer
11c exhibits a similar qualitative behavior to that of the
ortho compound (data not shown).
Strong changes over the entire spectrum of 11a are
observed when the pH is increased from 1.0 to 5.0 (Figure
3): the progressive blue shift of the low-energy band (λmax
332 nm) assigned to π-π* transitions is observed as well
as the decrease until complete disappearance of the weak
band lying near the visible (λmax 382 nm), which is highly
characteristic of the phenanthrolinium ion.27 These
variations are accompanied by the remaining of two
isosbestic points (277 and 327 nm). On the basis of
phenanthrolines’ photophysical properties,27 deprotona-
tion at the ring nitrogen atoms is responsible for these
spectral features. Likewise, in the same pH range, the
emission fluorescence spectra (inset, Figure 3) show the
disappearance of a broad band centered at 525 nm
assigned to the protonated form of the dibenzophen-
anthroline,27b,c and the concomitant appearance of a well-
structured band with three vibronic shoulders (437, 464,
and 496 nm) corresponding to the neutral form of the
aromatic nucleus. An isoemissive point is observed at
538 nm.
The same trends are observed for the p-quinacridine
11b but with some discrepancies as compared with the
ortho isomer: two distinct families of isosbestic points
are detected from the absorption spectra, which are
correlated to two pH ranges, i.e., 407 nm (pH 1.2-2.4;
Figure 5A) and 283 and 321 nm (pH 2.4-5.0; Figure 5B).
The fluorescence variations show also the existence of
two pH regions: below pH 2.4 a significant albeit weak
increase of the red-shifted emission is noted (Figure 5A,
inset), whereas enhancement of pH up to 5.0 induces the
disappearance of the red-shifted band and the appear-
ance of the fine structure of the deprotonated quinacri-
dine ring with an isoemissive point remaining at 492 nm
(Figure 5B, inset). These data indicate that two equi-
libria involving three species take place below pH 5.0
which are attributable to the deprotonation of the two
ring nitrogen atoms. This is in accordance with the
higher pKa value of the N1 nitrogen of the 4,7-phenan-
throline (pKa ) 2.5),27e with respect to that of the [1,10]-
phenanthroline. However the weak intensity of the
spectral variations occurring below pH 2.4 is likely to
reflect the small proportion of the fully protonated species
thus accounting for the low basicity of N1 in the quina-
cridine ring.
The variations of intensities of both absorption and
fluorescence of 11a at various wavelengths are repre-
sented as a function of pH (Figure 4) and are consistent
with the occurrence of one equilibrium process corre-
(27) (a) Badger, G. M.; Walker, I. S. J . Chem .Soc. 1956, 122. (b)
Henry, M. S.; Hoffman, M. Z. J . Phys. Chem. 1979, 83, 618. (c)
Armaroli, N.; De Cola, L.; Balzani., V.; Sauvage, J .-P.; Dietrich-
Buchecker, C. O.; Kern, J .-M.; Sauvage, J .-P. J . Chem. Soc., Faraday
Trans. 1992, 88, 553. (d) Dietrich-Buchecker, C. O.; Sauvage, J .-P;
Armaroli, N.; Ceroni, P.; Balzani., V. New J . Chem. 1996, 20, 801. (e)
Perkampus, H.-H.; Ko¨hler, H. Z. Elektrochem. 1960, 64, 365.

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5465
Ta ble 1. Gr ou n d Sta te P Ka Va lu es a n d Assign m en ts for
Mon om er ic Qu in a cr id in es
a
pKa
N1
N2
N3, N4
compound
11a (o)
(ring)
(ring)
(sidearms)
b
3.5 (3.6)
3.5 (3.3)
3.3 (3.5)
4.9
5.3
4.3
8.9 (9.0)e
8.2 (8.5)e
8.5 (8.7)e
11b (p)
11c (m)
<1.0c
b
[1,10]phen (o)d
[4,7]phen (p)d
[1,7]phen (m)d
-1.4
2.5
0.75
a
pKa values have been determined according to the equation
pKa ) [pH - log(Aa - A/A - Ab)] where Aa,b are the absorption (or
fluorescence) intensity of the acid and basic forms and A the
absorption (or fluorescence) intensity at an intermediate pH; the
b
values in parentheses are obtained from fluorescence data. Non-
measurable in the pH range examined. c Estimated from the weak
d
spectral variations, see text. See ref 27e. e Average values, see
text.
F igu r e 7. Normalized changes in absorbance and in fluores-
cence intensity (λexc ) 324 nm) of macrocycles 7a and 9 (1.0 ×
10-5 M) as a function of pH: (A) compound 7a , absorbance at
386 nm ([) and fluorescence intensity at 443 nm (0); (B)
compound 9, absorbance at 383 nm ([) and fluorescence
intensity at 444 nm (0).
F igu r e 6. Normalized changes in fluorescence intensity of
compounds 11a at 437 nm ([) (λexc ) 324 nm); 11b at 407 nm
(∆) (λexc ) 327 nm), and 11c at 425 nm (9) (λexc ) 327 nm) in
the pH range 7.0-10.0.
ecules formed by the deprotonation of the linkers. These
changes are characteristic of the deprotonation of the
amino side chains and lead to average pKa values around
8.5-9 for the two N atoms (N3, N4) (Table 1).
The pKa’s of monomers 11 determined from the spec-
tral variations are listed in Table 1. The good correlation
between the pKa values determined from either the
absorption or the emission spectral changes of 11 might
be interpreted in terms of slow rates of the proton
exchange in the excited state relative to the rate of the
fluorescence decay.27c The comparison of the pKa values
of the nitrogen atoms of compounds 11 with those of the
related phenanthrolines indicates a lower basicity of at
least 1 pKa unit for N2 nitrogen in the three series and
for N1 nitrogen in the case of 11b. The influence of the
external benzo cycles on the pKa is known to be weak,
and such a difference might be essentially attributed to
the electroattracting effect of the ammonium substitu-
ents.
Between pH 5.0 and 7.0 a leveling off of the spectral
variations is recorded for the three isomeric quina-
cridines, whereas a spectacular drop in the emission
intensities is recorded above pH 7.0 without modification
of the spectral shapes (Figure 6). This strong decrease
in fluorescence (90%) can be essentially attributed to a
quenching effect via photoinduced electron transfer (PET)
from the benzylic nitrogen lone pairs to the quinacridine
ring excited state as is commonly observed for amino-
substituted substituted aromatic compounds.28 More
moderate decrease in absorption (30-40%) of compounds
11 was observed at basic pH which may be explained in
terms of a π-stacking effect between the neutral mol-
In summary the determination of the pKa values and
the leveling off of the spectral intensities between pH 5.0
and 7.0 demonstrate that compounds 11 exist in their
side-chain diprotonated form in this pH range.
3. Deter m in a tion of th e p Ka of th e Ma cr ocyclic
Bisq u in a cr id in es 7-9. The macrocyclic bisquina-
cridines contain multiple protonation sites which render
difficult the determination of the pKa’s by spectroscopic
methods. However the comparison of the spectroscopic
properties of the macrocycles with those of the monomers,
as a function of pH, with the help of our previous works
on other cyclobisintercalands,7 gives an indication of the
dominant species in given pH domains.
Indeed the pH dependence of both absorption and
fluorescence spectra of macrocycle 7a appeared roughly
similar to that of the corresponding monomer 11a (Figure
7A). A pH region between 2.5 and 3.5 corresponding to
the deprotonation of the ring nitrogen atoms is clearly
determined from these variations. The central NH of
diethylenetriamine is known to have a remarkably weak
basicity (pKa ) 2.5-3.0), and only slight spectral varia-
tions are expected to result from its deprotonation. This
phenomenon is thus supposed to be hidden by the strong
changes induced by the deprotonation of the quinacridine
nuclei. The drop in fluorescence intensities at basic pH
induced by the deprotonation of the four benzylic nitro-
gens of 7a takes place between pH 6.5 and 8.0, shifted
by about 1 unit toward the acidic pH as compared to
monomer 11a (Figure 7A); this indicates the lower
basicity of the benzylic NHs in the macrocyclic structure
(28) (a) De Silva, A. P.; De Silva, S. A. J . Chem. Soc, Chem. Commun.
1986, 1709. (b) Czarnik, A. W. Acc. Chem. Res. 1994, 27, 302.

5466 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
Ta ble 2. Mola r Extin ction Coefficien ts (E) a n d
F lu or escen ce Qu a n tu m Yield s (ΦF ) of Mon om er s 11a -c
a n d Ma cr ocyclic Bisqu in a cr id in es 7-9 Mea su r ed in
Ca cod yla te Bu ffer 1 m M (p H 6.0, 4 m M Na Cl, 20 °C)
ꢀ/dm3 mol-1 cm-1
compound
(λmax/nm)
(× 10-4
)
ΦF
a
11a
11b
11c
7a
8
9
316, 324
305, 327
312, 327
315, 327
315, 327
316, 327
299, 324
6.2, 5.8
4.2, 4.6
3.9, 5.0
9.1, 7.2
8.5, 7.1
8.9, 8.2
6.2, 4.6
0.10
0.25
0.12
0.03
0.04
0.04
0.006
7b
a
Determined using quinine disulfate in 0.05 N H2SO4 (ΦF
0.55) and anthracene in ethanol (ΦF ) 0.27) as references.
)
F igu r e 8. Absorption spectra and (inset) normalized emission
spectra of 11a (-‚-) (8 × 10-6 M) (λexc ) 316 nm) and
macrocycles 7a (s) (4 × 10-6 M) (λexc ) 315 nm) and 9 (- - -) (4
× 10-6 M (λexc ) 316 nm) in 1 mM cacodylate buffer (pH 6.0;
4 mM NaCl, 20 °C). For the sake of clarity the absorption and
emission spectra of 8 which are similar to those of 7a have
been omitted.
as already observed for other cyclobisintercalands.7b,c
Therefore, on the basis of these results we may expect
that the tetraprotonated form of macrocycle 7a will
predominate in the pH range 5.0-6.0 which is confirmed
by the plateau of the spectral intensities in this region
(Figure 7A). The same pH domains are deduced from
the titration curve of macrocycle 8 (data not shown).
In the case of macrocycle 9 a similar behavior is
observed at acidic pH (2.5-3.5) with respect to 7a (Figure
7B). On the other hand the deprotonation of the propy-
lene linkers arises at a higher pH range (7.0-9.0), in
agreement with the higher basicity of the free dipropy-
lenetriamine (8 < pKa’s <10). One may conclude that 9
exists mainly as an hexaprotonated species between pH
5.0 and 7.0.
The pH dependence of the absorbance of macrocycle
7b similarly indicates the predominance of the tetraca-
tionic form near neutrality (pH 6.0). The fluorescence
changes are more difficult to interpret owing to the
particular photoreactivity of compound 7b (see next
section).
4. Sp ectr oscop ic Da ta a n d Molecu la r Sh a p es. A
comparative study of the spectroscopic properties of the
monomers and the dimers has been carried out at pH
6.0 in order to evaluate the extent of intramolecular
interactions between the two quinacridine units in the
macrocyclic structures. Our purpose was to gain infor-
mation on the conformation of the macrocyclic compounds
in the pH domain where they exist in a unique form and
where biological substrate binding experiments are to be
conducted.
F igu r e 9. Absorption spectra and (inset) normalized emission
fluorescence spectra of 11b (- ‚ -) (8 × 10-6 M) (λexc ) 327
nm) and 7b (s) (4 × 10-6 M) (λexc ) 324 nm) in 1 mM
cacodylate buffer (pH 6.0; 4 mM NaCl, 20 °C).
2). These spectral features, which have been observed
for other cyclobisintercalands,7 are characteristic of
bichromophoric systems;29 they are attributed to weak
intramolecular interactions between the quinacridine
nuclei and reflect a more or less mutual parallel orienta-
tion of the two rings. On the other hand, the absence of
a bathochromic shift shows that there is no significant
electronic interaction between the aromatic units.29c,d
Examination of fluorescence data indicates some dif-
ferences between the ortho and the para series. The
emission spectra of macrocycles 7a , 8, and 9 display a
shape similar to that of monomer 11a (Figure 8, inset)
with a slight red shift of the band already observed in
related systems; by contrast they exhibit much lower
quantum yields (Table 2). In accordance with the hypo-
chromism of the absorption, these data support the
existence of intramolecular interactions between the
aromatic rings in the excited state and are thus repre-
sentative of the dimeric macrocyclic structure. On the
other hand, the emission spectrum of 7b shows important
distortions from the shape of monomeric compound 11b
(Figure 9, inset): the monomer emission has almost
completely disappeared at the expense of a broad band
strongly red-shifted (474 nm) which exhibits a very low
quantum yield [ΦF(11b)/ΦF(7b) ) 40] (Table 2). This
band is ascribable to an excimer emission as excitation
spectra scanned at various wavelengths are similar to
the absorption spectrum of 7b. The stabilization of an
The absorption spectra of cyclic compounds 7-9 (Fig-
ures 8 and 9) display similar behavior as compared to
their related monomers: the π-π* band centered at 315
nm is not shifted but the fine structure is affected and
presents a strong hypochromism (ꢀdimer , 2ꢀmonomer) (Table
(29) (a) Castellan, A.; Desvergne, J .-P.; Bouas-Laurent, H. Nouv.
J . Chem. 1979, 3, 231. (b) Hinschberger, J .; Desvergne, J .-P.; Bouas-
Laurent, H.; Marsau, P. J . Chem. Soc., Perkin Trans. 2 1990, 93. (c)
Bouas-Laurent, H.; Castellan, A.; Daney, M.; Desvergne, J.-P.; Guinand,
P.; Marsau, P. Riffaud, M. H. J . Am. Chem. Soc. 1986, 108, 315. (d)
Misumi, S.; Otsubo, T. Acc. Chem. Res. 1978, 11, 251.
(30) De Schryver, F. C.; Collart, P.; Vandendriessche, J.; Goedeweeck,
R.; Swinnen, A.; Van der Auweraer, M. Acc. Chem. Res. 1987, 20, 159.

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5467
Ta ble 3. NMR Ch em ica l Sh ifts (p p m ) of Mon om er ic a n d
Ma cr ocyclic Dim er ic Qu in a cr id in es a t p H 6.0
Ta ble 4. NMR Ch em ica l Sh ifts (p p m ) of Mon om er ic a n d
Dim er ic Qu in a cr id in es a t Acid ic p H
D2O/TFA, pH 0.3a
compd
Ha (∆δ)b
Hb (∆δ)
Hc (∆δ)
Hd (∆δ)
He (∆δ)
11a
7a
8.20
7.91
8.60
8.21
8.45
8.15
9.37
8.95
8.08
7.75
(-0.29)
(-0.39)
(-0.30)
(-0.42)
10.83
10.60
(0.23)
(-0.33)
11b
7b
8.49
8.63
8.87
8.92
D2O, pH 6.0a
8.40
(-0.09)
8.44
(-0.19)
8.72
(-0.15)
8.77
(-0.15)
compd
Ha (∆δ)b
Hb (∆δ)
Hc (∆δ)
Hd (∆δ)
He (∆δ)
a
All solutions are 3 mM in D2O, and the pH was adjusted to
11a
7a
7.79
7.59
8.28
7.96
8.0
7.37
8.53
7.12
7.53
6.62
b
0.3 with CF3COOD. ∆δ ) difference of chemical shifts between
the macrocyclic dimer and the related monomer.
(-0.20)
7.45
(-0.32)
7.98
(-0.63)
7.79
(-1.41)
7.43
(-0.91)
7.09
8
9
(-0.34)
7.52
(-0.27)
7.03
(-0.30)
8.05
(-0.23)
7.42
(-0.30)
7.40
(-0.60)
7.70
(-1.10)
8.24
(-0.29)
8.25
(-0.44)
7.40
(-0.13)
7.39
which contributes to the shielding observed for the
macrocycles. However, aggregation of quinacridines in
water has never been detected at lower concentrations
and it seems to be a phenomenon of marginal importance,
in contrast to the high tendency of planar aromatic
cations to aggregate in aqueous media.16,31
11b
7b c
a
All solutions are 5 mM in D2O, and the pH was adjusted to
b
6.0 with pyridine-d5/CF3COOD buffer. ∆δ ) difference of chemi-
cal shifts between the macrocyclic dimer and the related monomer.
Analysis of macrocycle 7a at more acidic pH in D2O/
DCl reveals some difficulties due to large broadening of
the signals. This effect detectable from pH 3.5 is more
pronounced as the pH decreases to give completely
unresolved spectra around pH 1.0 while no precipitation
was observed. On the contrary, a well-resolved spectrum
of 7a is recorded in a mixture of D2O/CF3COOD (pH )
0.3). Compounds 8 and 9 exhibit the same behavior, but
this effect, which may be attributed to proton exchange
processes, has never been observed with monomer 11a
or with other cyclobisintercalands. These results may
indicate the formation of associations displaying proton
exchange when the counteranion is chloride. Downfield
shifts of all aromatic proton signals of 11a and 7a are
observed at acidic pH as expected from protonation of
the ring nitrogens. On the other hand the magnitudes
of the ∆δ values are considerably reduced as compared
to those recorded at pH 6.0 (Table 4). This illustrates
the decrease of the stacking effects between the quina-
cridine units both inter- and intramolecularly due to the
repulsion between the supplementary positive charges
on the side chains and on the aromatic moieties of the
molecules.
c Nonmeasurable, see text.
excimer is strongly dependent on the overlap between
the two chromophores.30 This result suggests, therefore,
that within the lifetime of the excited state, 7b exists as
a flattened conformation with at least partial stacking
of the aromatic units. Moreover repeated scans on a
sample of 7b at pH 6.0 induce dramatic changes of the
emission spectrum both in shape and intensity, revealing
the occurrence of photoinduced processes. No significant
variation of the fluorescence of 11b is observed in the
same conditions and the behavior of 7b under irradiation
may be attributed to photochemical reactivity resulting
from the macrocyclic structure.
Additional information about interchromophoric inter-
actions in the macrocycles is provided by 1H NMR
spectral data: a comparative study of the proton reso-
nances for cyclic and monomeric quinacridines has been
carried out in D2O at pH 6.0 where the macrocycles and
the monomers contain uncharged quinacridine moieties
and at acidic pH (<1.0) where the compounds are fully
protonated.
Compound 7b exhibits very poor solubility in D2O
whatever the pH. In this case significant intermolecular
interactions between the macrocyclic molecules are thus
likely to take place in addition to the strong intramo-
lecular interactions indicated by the fluorescence proper-
ties. However, 7b is soluble in the D2O/CF3COOD
mixture which emphasizes the ability of this medium to
prevent intermolecular associations. As already observed
for 7a , the spectrum of 7b at acidic pH shows only modest
shifts of the proton resonances of the macrocycle with
respect to those of the monomer 11b (Table 4); this
confirmed the weak interactions between the two quina-
cridine units when the macrocycles are fully protonated.
The marked differences in physicochemical properties
between the macrocycles containing o-quinacridine units
(7a and 8) and compound 7b built from p-quinacridine
moieties leads to a conclusion of the existence of different
conformations with various interchromophoric distance.
These structural differences could induce interesting
binding preferences in particular toward biological spe-
cies such as nucleotides and nucleic acids.
At pH 6.0, the aromatic proton resonances are strongly
shifted upfield in the spectrum of 7a , with respect to that
of 11a , especially for Hc-e (Table 3). Similarly strong
shieldings are recorded for anologue 8 but the trend is
much weaker for macrocycle 9. Such results are coherent
with the occurrence of some interaction between the two
quinacridine units for the tetracationic forms of 7a and
8. These interactions are diminished evidently for 9 due
to the higher length of the two amino linkers and to the
hexaprotonation of the bridges which should enhance the
interchromophoric distance. This behavior can be inter-
preted in terms of conformational flexibility of these
dimeric molecules and allows for the prediction that a
semiclosed conformation24 would be favored in water near
the neutrality for the macrocycles possessing diethylen-
etriamine linkers whereas a more open structure is likely
to exist for the dimers bridged by propylenetriamine
chains. However an increase in concentration of 7a from
1 to 8 mM induces a continuous shielding of all aromatic
protons, and the same concentration dependence is
recorded for monomer 11a . Though the magnitude of
this effect is weak (-0.4 ppm at the maximum), it is
nonetheless indicative of self-association of quinacridine
11a and bisquinacridine 7a at millimolar concentration
(31) Pilch, D. S.; Martin, M.-T.; Nguyen, C. H.; Sun, J .-S; Bisagni,
E.; Garestier, T.; He´le`ne, C. J . Am. Chem. Soc. 1993, 115, 9942.

5468 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
2-amino-5-methylbenzoic acid (10.00 g, 66.2 mmol), copper
bronze (420 mg, 6.6 mmol), CuI (1.01 g, 5.3 mmol), K2CO3 (9.14
g, 66.2 mmol), and n-pentanol (100 mL) was stirred under
reflux for 24 h. After the solvent was removed in vacuo,
methanol was added and the solution was filtered through
Celite. Methanol was evaporated by 75%, and an equal
volume of water was added. The solution was treated dropwise
with concentrated hydrochloric acid until a precipitate ap-
peared. The dark precipitate was filtered and stirred vigor-
ously in ethyl ether (300 mL); the suspension was filtered and
the precipitate again stirred in ether (the operation was
repeated twice). Combined ether fractions were distilled off
until a slightly colored precipitate appeared. A yellow solid
was then obtained after filtration. The crude product was
recrystallized from ethanol and water yielding 4.0 g (40%) of
a pale yellow powder: mp 220 °C; 1H NMR (DMSO-d6) δ 2.19
(s, 6 H), 6.93 (d, J ) 8.5 Hz, 2 H), 7.08 (m, 2 H), 7.15 (dd, J )
8.5 and 2 Hz, 2 H), 7.38 (m, 2 H), 7.65 (d, J ) 2 Hz, 2 H), 9.40
(s, 2 H), 12.8 (br s, 2 H) ppm; IR (Nujol mull) 3344, 3328,
3300-3000, 1660 cm-1. Anal. Calcd for C22H20N2O4: C, 70.20;
H, 5.36; N, 7.44. Found: C, 70.05; H, 5.36; N, 7.38.
Con clu sion
The efficient synthesis of substituted angular quina-
cridines described here is applicable to the preparation
of a large number of substituted compounds and requires
only cheap and accessible starting materials. It should
be possible to further expand the versatility of this
approach to the synthesis of analogues bearing protona-
table pendant chains in various positions by using
functional dihalogenated derivatives or differently sub-
stituted aminobenzoic acids. The dichloro intermediates
offer also an opportunity to build functionalized quina-
cridines. Finally the possibility of obtaining monocon-
densed anthranilic acids as major products in the Ull-
mann-Goldberg reaction when a dibromobenzene is used
instead of a diiodo derivative makes this route attractive
for the preparation of unsymmetrically substituted quina-
cridines.
The availability of isomeric quinacridines 11 will be
very helpful for the systematic study of the steric and
electronic requirements for the stabilization of ordered
nucleic structures such as duplexes and triplexes through
a putative intercalative mode. Furthermore the potential
of compounds 11 to induce damages in DNA by means
of photochemically triggered cleavages is currently under
examination.
The cationic macrocyclic bisquinacridines containing
cavities of large size and variable charge, shape, and
hydrophobic character provide a tool for the recognition
of nucleobases associated through various H-bonding
patterns. By analogy to macrocyclic bisacridines that
have been shown to discriminate between single-stranded
and double-stranded DNA sequences,32 these compounds
could also selectively recognize nucleic acids secondary
structures such as loops or bulges.
In addition the space delineated by the macrocyclic
bisquinacridine framework could be appropriate for com-
bining catalytic and binding functionalities; to this end
one may consider complexing metal ions or attaching
functional groups to the macrocycle for inducing a
catalytic event on the bound substrate. Such perspec-
tives represent attractive developments for the future.
3b and 3c were obtained in the same manner from 1,4-
diiodobenzene and 1,3-diiodobenzene, respectively.
5,5′-Dim et h yl-2,2′-(1,4-p h en ylen ed ia m in o)b isb en zoic
a cid (3b): pale yellow powder (yield 60%); decomposition g
1
275 °C; H NMR (DMSO-d6) δ 2.20 (s, 6 H), 7.08 (d, J ) 8.5
Hz, 2 H), 7.17 (2 s, 4 H), 7.20 (dd, J ) 8.5 and 1.5 Hz, 2 H),
7.68 (d, J ) 1.2 Hz, 2 H) ppm; 13C (DMSO-d6) δ 19.9 (CH3),
112.4 (Cq), 114.0 (CH), 122.7 (CH), 125.7 (Cq), 131.5 (CH),
134.9 (CH), 136.2 (Cq), 145.4 (Cq), 169.8 (Cq) ppm; IR (Nujol
mull) 3323, 2729, 2627, 2547, 1667, 1584 cm-1. Anal. Calcd
for C22H20N2O4‚0.5H2O: C, 68.56; H, 5.49; N, 7.27. Found: C,
68.48; H, 5.37; N, 6.91.
5,5′-Dim et h yl-2,2′-(1,3-p h en ylen ed ia m in o)b isb en zoic
a cid (3c): yellow powder (yield 45%); decomposition g 260
1
°C; H NMR (DMSO-d6) δ 2.22 (s, 6 H), 6.79-6.83 (dd, J ) 8
and 2 Hz, 2 H), 6.99 (s, 1 H), 7.20-7.24 (m, 5 H), 7.69 (s, 2 H)
ppm.
13,14-Dih yd r od iben zo[b,j][1,10]p h en a n th r olin e-5,8-d i-
on e (4a ). 3a (10.39 g, 27.6 mmol) was stirred with 95%
sulfuric acid (150 mL) at 100 °C for 1 h. The cool mixture
was slowly poured into cold water (250 mL). The orange
precipitate was filtered off and washed with boiling water and
1 mM KOH until the pH of the filtrate became 3-4. The
product was washed with ethanol and ether and dried under
vacuum at 70 °C, yielding 9.0 g (95%) of a yellow powder
1
(hygroscopic): mp > 400 °C; H NMR (DMSO-d6) δ 2.46 (s, 6
H), 7.67 (s, 4 H), 7.99 (s, 2 H), 8.07 (s, 2 H), 11.62 (br s, 2 H)
ppm; IR (Nujol mull) 3375-3000, 1668, 1632 cm-1; MS (EI+,
I ) 4.5 V), m/z 340 (M+•).
Exp er im en ta l Section
All commercially available chemicals were reagent grade
and used without further purification. THF and dioxane were
distilled over classical drying agents before use. 1H and 13C
NMR spectra were recorded on a Bruker AC 200 spectrometer.
Attributions were made by two-dimensional experiments (Cq
) quaternary carbon). NMR spectra of D2O solutions were
monitored using DSS as the reference; solutions at pH ) 6.0
have been obtained using a pyridine-d5/CF3CO2D buffer (6.5
× 10-2 M). UV-vis experiments were monitored on a Beck-
mann DU 640 spectrophotometer. Fluorescence measure-
ments were performed on a Spex Fluoromax spectrophotom-
eter equipped with a Hamamatsu R928 photomultiplier (PM),
using a thermostated cell holder; the data were corrected for
the response of the PM. Melting points were determined on
a Electrothermal 9100 apparatus. IR spectra were obtained
on a Bruker Vector 22 FT-IR spectrometer. Mass spectrometry
was performed at the Laboratoire de Chimie Structurale
Organique et Biologique, Universite´ Pierre et Marie Curie
(Paris). The microanalyses were performed at the Service
Re´gional de Microanalyse de l′Universite´ Pierre et Marie
Curie.
13,14-Dich lor o-2,11-d im e t h yld ib e n zo[b,j][4,7]p h e n -
a n th r olin e (4b). 3b (1.0 g, 2.66 mmol) and POCl3 (10 mL,
0.106 mol) were refluxed under nitrogen for 3.5 h. POCl3 was
removed under vacuum, CH2Cl2 (50 mL) was added, and the
dark solution was slowly poured into cold 15% NH4OH (30
mL). The organic layer was decanted, and the aqueous layer
was extracted with CH2Cl2 (3 × 25 mL). The organic solutions
were mixed, dried over sodium sulfate, and evaporated. The
brown product was recrystallized from CHCl3, yielding 388 mg
1
(39%) of yellow prisms: mp 252 °C; H NMR (CDCl3) δ 2.66
(s, 6 H), 7.72 (dd, J ) 8.5 and 1.7 Hz, 2 H), 7.81 (s, 2 H), 8.15
(d, J ) 8.5 Hz, 2 H), 8.26 (s, 2 H) ppm; 13C (CDCl3) δ 22.0,
120.7, 123.6, 124.9, 129.0, 132.8, 133.3, 138.1, 141.0, 146.6,
150.0 ppm; UV-vis (CH2Cl2) λ (ꢀ) 249 (42 000), 325 (57 000),
376 (14 000) (M-1 cm-1). Anal. Calcd for C22H14N2Cl2‚
0.1CHCl3: C, 68.39; H, 3.64; N, 7.22. Found: C, 68.35; H, 3.56;
N, 7.28.
13,14-Dich lor o-2,10-d im e t h yld ib e n zo[b,j][1,7]p h e n -
a n th r olin e (4c). 4c was obtained in the same manner as
above for 4b: yellow crystals (yield: 33%); mp 260 °C; 1H NMR
(CDCl3/CD3OD) δ 2.45 (s, 3 H), 2.47 (s, 3 H), 7.49 (d, J ) 2.8
Hz, 1 H), 7.54 (d, J ) 2.8 Hz, 1 H), 7.66 (d, J ) 9.8 Hz, 1 H),
7.88 (d, J ) 8.7 Hz, 1 H), 7.93 (s, 1 H), 8.05 (d, J ) 8.8 Hz, 1
H), 8.18 (d, J ) 9.9 Hz, 1 H), 8.28 (s, 1 H) ppm.
5,5′-Dim et h yl-2,2′-(1,2-p h en ylen ed ia m in o)b isb en zoic
Acid (3a ). A mixture of 1,2-diiodobenzene (8.73 g, 26.5 mmol),
3,10-Dim eth yld iben zo[b,j][1,10]p h en a n th r olin e (5a ).
Dry 4a (3.04 g, 8.9 mmol) and n-pentanol (350 mL) were
(32) Slama-Schwok, A.; Teulade-Fichou, M.-P.; Vigneron, J .-P.;
Lehn, J .-M.; Taillandier, E. J . Am. Chem. Soc. 1995, 117, 6822.

Cyclobisintercaland Macrocycles
J . Org. Chem., Vol. 62, No. 16, 1997 5469
heated to reflux. Sodium (8.18 g, 356 mmol) was added in
small portions, and the solution was refluxed for about 10 h
after the end of the addition. The pentanol was removed under
vacuum, and the residue was taken up in CH2Cl2 and water.
The emulsion was filtered in order to recover the unreacted
quinacridone. The biphasic filtrate was decanted, and after
being washed with water, 1 N HCl, and H2O again, the organic
solution was dried over MgSO4 and evaporated, giving a red
powder containing 5a and a hemireduced compound (major
product). This mixture was reoxidized as follows: it was
refluxed in ethanol (120 mL), and FeCl3 (5.1 g, 19 mmol)
dissolved in water (60 mL) was slowly added. The solution
was refluxed for about 15 h, 15% NH4OH was added to the
cooled solution, and the black precipitate was filtered and
washed with methanol. The alcoholic solvents were removed
under vacuum from the filtrate, and water was then extracted
with dichloromethane. The organic layer was dried over Na2-
SO4 and evaporated, giving a brown product that was recrys-
tallized from CHCl3, yielding 912 mg (33%) of yellow crystals:
washed with hexane to remove naphthalene and recrystallized
three times from CHCl3 and CH3OH, yielding 312 mg (56%)
of a yellow powder: mp > 400 °C; 1H NMR (CDCl3/CD3OD
5/1) δ 7.84 (s, 2 H), 8.30 (dd, J ) 9 and 2 Hz, 2 H), 8.59 (d, J
) 2 Hz, 2 H), 8.71 (d, J ) 9 Hz, 2 H), 8.90 (s, 2 H), 10.22 (s, 2
H); IR (Nujol mull) 1688, 1621 cm-1. Anal. Calcd for (C22H12
-
N2O2‚0.75CHCl3): C, 62.69; H, 2.96; N, 6.40. Found: C, 62.61;
H, 3.13; N, 6.51.
Compounds 6b and 6c were obtained in the same manner
from 5b and 5c respectively.
Dib en zo[b,j][4,7]p h en a n t h r olin e-2,11-d ica r b oxa ld e-
h yd e (6b): pale yellow powder (yield 55%); decomposition g
350 °C; 1H NMR (CDCl3/CD3OD 5/1) δ 8.28-8.34 (1 s + 2 d, 6
H), 8.72 (s, 2 H), 9.78 (s, 2 H), 10.25 (s, 2 H); IR (Nujol mull)
1697, 1615 cm-1. Anal. Calcd for C22H12N2O2‚0.22CHCl3: C,
73.60; H, 3.40; N, 7.73. Found: C, 73.63; H, 3.47; N, 7.59.
Dib en zo[b,j][1,7]p h en a n t h r olin e-2,10-d ica r b oxa ld e-
h yd e (6c): yellow powder (yield 60%); mp 320-330 °C
1
1
(decomposition); H NMR (DMSO-d6) δ 7.99 (d, J ) 9.4 Hz, 1
mp 330-335 °C; H NMR (CDCl3/CD3OD 5/1) δ 2.56 (s, 6 H,
H), 8.30 (m, 4 H), 8.43 (d, J ) 9 Hz, 1 H), 8.66 (s, 1 H), 9.09 (s,
1 H), 9.27 (s, 1 H), 10.24 (s, 1 H), 10.25 (s, 1 H), 10.33 (s, 1 H)
ppm; IR (Nujol mull) 1696, 1636, 1606 cm-1. Anal. Calcd for
CH3(3/10)), 7.59 (s, 2 H, H(6/7)), 7.67 (dd, J ) 9 and 2 Hz, 2 H,
H(2/11)), 7.72 (d, J ) 2 Hz, 2 H, H(4/9)), 8.43 (d, J ) 9 Hz, 2 H,
H(1/12)), 8.47 (s, 2 H, H(5/8)) ppm; 13C NMR (CDCl3/CD3OD 5/1)
δ 21.9 (CH3), 126.5 (CH), 126.7 (CH), 127.7 (Cq), 128.4 (Cq),
130.0 (CH), 133.2 (CH), 135.0 (CH), 137.6 (Cq), 146.9 (Cq),
147.1 (Cq) ppm; UV-vis (CHCl3) λmax (ꢀ) 244 (52 000), 270
(16 000), 314 (39 000), 326 (50 000), 351 (23 000) nm (M-1
cm-1); fluorescence (CHCl3, λexc ) 326 nm) λem 422, 448, 479,
511 nm. Anal. Calcd for C22H16N2: C, 85.69; H, 5.23; N, 9.08.
Found: C, 85.53; H, 5.20; N, 9.01.
C
22H12N2O2‚0.6CHCl3: C, 66.54; H, 3.11; N, 6.87. Found: C,
66.14; H, 3.73; N, 6.31.
2,5,8,25,28,31-H e xa a za [9,9](3,10)d ib e n zo[b,j][1,10]-
p h en a n th r olin op h a n e (7a ). 6a (200 mg, 0.60 mmol) was
dissolved in an anhydrous mixture of 4/1 CH2Cl2/MeOH (500
mL). Diethylenetriamine (61 mg, 0.60 mmol) dissolved in the
same mixture of solvents (50 mL) was added dropwise for 2.5
h at room temperature, and the resulting solution was stirred
for 4 h after the end of the addition. The solvents were
distilled off to give the tetraimine as a yellow powder (95%
crude yield) that was used without further purification. It was
dissolved in 1/1 CH2Cl2/MeOH (100 mL), and the stirred
mixture was cooled to 0 °C. NaBH4 (56 mg, 1.49 mmol) was
added, and the solution was stirred at 0 °C for 2.5 h and at
room temperature for 30 min. The solvents were removed in
vacuo, and the residue was washed with water and recrystal-
lized from CHCl3 and CH3OH, giving 7a as a pale powder.
7a ,HCl was obtained in the following manner: 1 N HCl was
added to the powder, and the solution was heated and
precipitated with ethanol, yielding 95.5 mg (27%) of an orange
2,11-Dim eth yld iben zo[b,j][4,7]p h en a n th r olin e (5b). 4b
(200 mg, 0.53 mmol) in dry THF (10 mL) was added dropwise
under nitrogen to a refluxing solution of LiAlH4 (161 mg, 4.2
mmol) in dry THF (5 mL) for 30 min. It was refluxed for 10
h more, and the deep blue solution was allowed to cool at room
temperature. The flask was put in an ice bath, and the LiAlH4
in excess was slowly hydrolyzed with 1/1 THF/H2O. THF was
removed in vacuo, aqueous potassium tartrate was added, and
the solution was extracted with CH2Cl2. After drying over Na2-
SO4, an orange-red solid was obtained, containing a mixture
of 5b and hydrogenated derivatives. This mixture was reoxi-
dized in the same manner as above for 5a with FeCl3 (0.6 g,
2.1 mmol). The crude product was recrystallized from CHCl3
and CH3OH, giving 102 mg (62%) of pale yellow needles: mp
345 °C (decomposition); 1H NMR (CDCl3/CD3OD 2/1) δ 2.59
(s, 6 H, CH3), 7.65 (dd, J ) 8.5 and 1.7 Hz, 2 H, H(3/10)), 7.86
(s, 2 H, H(1/12)), 8.07 (d, J ) 8.5 Hz, 2 H, H(4/9)), 8.07 (s, 2 H,
H(6/7)), 9.35 (s, 2 H, H(13/14)) ppm; 13C NMR δ 21.7 (CH3(2/11)),
123.8 (Cq), 126.8 (CH(1/12)), 127.0 (Cq), 128.2 (CH(6/7)), 130.3
(CH(13/14)), 133.3 (CH(4/9)), 133.6 (CH(3/10)), 137.3 (Cq), 146.7 (Cq),
148.0 (Cq); UV-vis (CHCl3) λ (ꢀ) 248 (70 000), 314 (48 000),
332 (54 000), 361 (14 500) nm (M-1 cm-1); fluorescence (CHCl3,
λexc ) 332 nm) λem 411, 421, 436, 463, 495 nm. Anal. Calcd
for C22H16N2‚0.09CHCl3: C, 83.14; H, 5.08; N, 8.78. Found:
C, 83.18; H, 5.19; N, 8.43.
2,10-Dim eth yld iben zo[b,j][1,7]p h en a n th r olin e (5c). 5c
was obtained in the same manner as above for 5b: white
crystals (yield 38%); mp 230 °C; 1H NMR (CDCl3/CD3OD) δ
2.49 (s, 3 H, CH3(10)), 2.53 (s, 3 H, CH3(2)), 7.56 (d, 1 H, H(11)),
7.58 (s, 1 H, H(9)), 7.60 (d, 1 H, H(3)), 7.71 (s, 1 H, H(6)), 7.74 (s,
1 H, H(7)), 7.79 (s, 1 H, H(1)), 8.00 (d, 1 H, H(4)), 8.09 (d, 1 H,
H(12)), 8.30 (s, 1 H, H(8)), 9.79 (s, 1 H, H(14)) ppm; 13C NMR
(CDCl3/CD3OD) δ 21.7 (2 CH3(2/10)), 124.6 (Cq), 125.7 (Cq), 126.7
(CH(9)), 127.2 (Cq), 127.6 (Cq), 127.7 (CH(3)), 127.9 (CH(1)), 128.1
(CH(6)), 129.0 (CH(12)), 131.4 (CH(7)), 133.1 (CH(11)), 133.3
(CH(14)), 133.8 (H(4)), 134.8 (CH(8)), 136.7 (Cq), 136.8 (Cq), 146.5
(Cq), 146.9 (Cq), 147.2 (Cq), 150.2 (Cq) ppm; UV-vis (CHCl3)
λ (ꢀ) 246 (75 000), 315 (50 000), 329 (56 000), 350 (29 000) nm
(M-1 cm-1); fluorescence (CHCl3, λexc ) 329 nm) λem 415, 424,
440, 468, 502 nm. Anal. Calcd for C22H16N2‚0.2CHCl3: C,
80.25; H, 4.91; N, 8.43. Found: C, 80.16; H, 4.99; N, 8.49.
Diben zo[b,j][1,10]p h en a n t h r olin e-3,10-d ica r boxa ld e-
h yd e (6a ). 5a (507 mg, 1.64 mmol), SeO2 (401 mg, 3.62 mmol),
and naphthalene (10 g) were heated to reflux for 2.5 h. The
residue was suspended in CH2Cl2/MeOH, decanted, and fil-
tered off. The filtrate was evaporated, and the residue was
1
powder: salt decomposition g 150 °C; H NMR (D2O, pH )
6.0, [7a ] ) 5 mM) δ 3.22 (m, 4 H), 3.44 (m, 4 H), 4.28 (s, 4 H),
6.62 (s, 2 H, H(6/7)), 7.12 (s, 2 H, H(5/8)), 7.37 (s, 2 H, H(4/9)), 7.59
(d, J ) 8 Hz, 2 H, H(2/11)), 7.96 (d, J ) 8 Hz, 2 H, H(1/12)); UV-
vis (H2O, pH ) 6.0) λ (ꢀ) 239 (91 000), 263 (65 000), 315
(91 000), 350 (30 000) nm (M-1 cm-1); fluorescence (H2O, pH
) 6.0, λexc ) 315 nm) λem 444, 472, 502 nm; MS (Electrospray,
MeOH/H2O 1/1) m/z 815.5 ([C52H50N10 + H]+), 408.25 ([C52H50N10
+ 2 H]2+/2). Anal. Calcd for (C52H50N10‚7HCl‚6H2O): C, 53.00;
H, 5.90; N, 11.89. Found: C, 53.05; H, 5.96; N, 11.95.
5,28-Dioxy-2,8,25,31-tetr aaza[9,9](3,10)diben zo[b,j][1,10]-
p h en a n th r olin op h a n e (8). 2,2′-Oxybis(ethylamine) dihy-
drochloride (197 mg, 1.11 mmol) and sodium hydroxide (111
mg, 2.78 mmol) were dissolved in anhydrous methanol (10
mL). After 3 h of stirring, the NaCl precipitate was filtered
off and methanol was removed in vacuo at room temperature.
CH2Cl2 was added, NaCl was again removed by filtration, and
the solvent was evaporated, yielding 116 mg (100%) of the free
amine that was used without further purification. Compound
8 was obtained in two steps in the same manner as above for
7a , from 2,2′-oxybis(ethylamine) (64 mg, 0.61 mmol) and 6a
(205 mg, 0.61 mmol). 8,HCl was formed by addition of 1 N
HCl and was purified by recrystallization from H2O and THF
to give 113 mg (33%) of an orange powder: decomposition of
the salt g 150 °C; 1H NMR (D2O, pH ) 6.0, [8] ) 5 mM) δ
3.48 (m, 4 H), 3.95 (m, 4 H), 4.12 (s, 4 H), 7.09 (s, 2 H, H(6/7)),
7.43 (s, 2 H, H(5/8)), 7.45 (d, J ) 8 Hz, 2 H, H(2/11)), 7.79 (s, 2 H,
H
(4/9)), 7.98 (d, J ) 8 Hz, 2 H, H(1/12)); UV-vis (H2O, pH ) 6.0)
λ (ꢀ) 238 (89 000), 266 (63 000), 315 (85 000), 349 (29 000) nm
(M-1 cm-1); fluorescence (H2O, pH ) 6.0, λexc ) 315 nm) λem
446, 473, 504 nm; MS (Electrospray, MeOH/H2O 1/1) m/z 818.0
([C52H48N8O2 + H]+), 409.51 ([C52H48N8O2 + 2 H]2+/2), 273.34

5470 J . Org. Chem., Vol. 62, No. 16, 1997
Baudoin et al.
([C52H48N8O2 + 3 H]3+/3). Anal. Calcd for (C52H48N8O2‚5HCl‚
6.5H2O): C, 55.94; H, 5.96; N, 10.04. Found: C, 55.91; H, 6.03;
N, 9.64.
3.02 (t, 4 H), 4.33 (s, 4 H), 7.57 (s, 2 H, H(6/7)), 7.85 (dd, J ) 9
and 2 Hz, 2 H, H(2/11)), 8.05 (d, J ) 2 Hz, 2 H, H(4/9)), 8.16 (d,
J ) 9 Hz, 2 H, H(1/12)), 8.78 (s, 2 H, H(5/8)) ppm; 13C NMR (D2O,
pH ) 2.1) δ 10.5 (CH3), 19.4 (CH2), 49.5 (CH2), 50.5 (CH2),
126.6 (CH), 127.0 (CH), 127.4 (Cq), 128.0 (Cq), 130.6 (CH),
131.8 (2 Cq), 134.1 (CH), 141.1 (CH), 143.1 (Cq) ppm; UV-vis
(H2O, pH ) 6.0) λ (ꢀ) 220 (42 000), 238 (52 000), 267 (37 000),
316 (62 000), 324 (58 000), 346 (34 000) nm (M-1 cm-1);
fluorescence (H2O, pH ) 6.0, λexc ) 316 nm) λem 438, 463, 495
nm. Anal. Calcd for (C28H30N4‚3HCl‚2H2O): C, 59.21; H, 6.57;
N, 9.86. Found: C, 59.19; H, 6.51; N, 9.60.
6,31-Dim et h yl-2,6,10,27,31,35-h exa a za [11,11](3,10)d i-
ben zo[b,j][1,10]p h en a n th r olin op h a n e (9). 9 was obtained
in two steps in the same manner as above for 7a , from 3,3′-
diamino-N-methyldipropylamine (90 mg, 0.62 mmol) and 6a
(200 mg, 0.59 mmol). 9,HCl was recrystallized twice from 1
N HCl and THF to give 100 mg (25%) of an orange powder:
1
decomposition of the salt g 150 °C; H NMR (D2O, pH ) 6.0,
[9] ) 5 mM) δ 1.87 (m, 8 H), 2.56 (s, 6 H), 2.95 (m, 16 H), 3.46
(s, 8 H), 7.40 (2 s, 8 H, H(6/7) + H(4/9)), 7.52 (d, J ) 9 Hz, 4 H,
H(2/11)), 8.05 (d, J ) 9 Hz, 4 H, H(1/12)), 8.24 (s, 4 H, H(5/8)); UV-
vis (H2O, pH ) 6.0) λ (ꢀ) 238 (83 000), 267 (60 000), 316
(89 000), 326 (81 000), 350 (36 000) nm (cm-1 M-1); fluores-
cence (H2O, pH ) 6.0, λexc ) 316 nm) λem 442, 470, 499 nm;
11b and 11c were obtained in the same manner from 6b
and 6c, respectively.
2,11-Bis((n -p r op yla m in o)m e t h yl)d ib e n zo[b,j][4,7]-
p h en a n th r olin e (11b): yellow powder (yield 52%): salt
decomposition g 150 °C; 1H NMR (D2O, pH ) 1.6) δ 0.97 (t, 6
H), 1.60-1.78 (m, 4 H), 3.04 (t, 4 H), 4.14 (s, 4 H), 6.79 (d, J
) 8.6 Hz, 2 H, H(3/10)), 7.14 (s, 2 H, H(6/7)), 7.33 (d, J ) 8.5 Hz,
2 H, H(4/9)), 7.57 (s, 2 H, H(1/12)), 8.26 (s, 2 H, H(13/14)) ppm; 13C
(D2O, pH ) 1.6) δ 10.6 (CH3), 19.3 (CH2), 49.5 (CH2), 50.3
(CH2), 121.6 (Cq), 125.3 (Cq), 125.8 (CH), 130.2 (CH), 130.9
(Cq), 132.2 (CH), 133.3 (CH), 133.9 (CH), 143.3 (Cq), 144.7 (Cq)
ppm; UV-vis (H2O, pH ) 6.0) λ (ꢀ) 247 (68 000), 305 (42 000),
327 (46 000) nm (M-1 cm-1); fluorescence (H2O, pH ) 6.0, λexc
MS (Electrospray, MeOH/H2O 1/1) m/z 900.5 ([C58H62N10
+
H]+), 450.5 ([C58H50N10 + 2H]2+/2). Anal. Calcd for (C58H62
-
N10‚8HCl‚7.5H2O): C, 52.54; H, 6.46; N, 10.56. Found: C,
52.62; H, 6.81; N, 10.06.
2,5,8,25,28,31-H e x a a za [9,9](2,11)d ib e n zo [b ,j][4,7]-
p h en a n th r olin op h a n e (7b). 7b was obtained in two steps
in the same manner as above for 7a , from 6b (192 mg, 0.57
mmol) and diethylenetriamine (61 mg, 0.59 mmol). Recrys-
tallization of crude 7b from CHCl3 and MeOH afforded a pale
powder that was recrystallized from 1 N HCl to give 111 mg
(33%) of 7b,HCl as a yellow-green powder: salt decomposition
) 327 nm) λem 407, 432, 459, 490 nm. Anal. Calcd for C28H30
-
N4‚3HCl‚1.3H2O: C, 60.56; H, 6.46; N, 10.09. Found: C, 60.54;
H, 6.53; N, 9.64.
1
g 150 °C; H NMR (D2O/CF3CO2D, pH ) 0.3) δ 3.74 (m, 16
2,10-Bis((n -p r op yla m in o)m e t h yl)d ib e n zo[b,j][1,7]-
p h en a n th r olin e (11c): yellow powder (yield 57%); salt
decomposition g 150 °C; 1H NMR (D2O, pH ) 2.7) δ 0.85-
0.95 (m, 6 H), 1.60-1.74 (m, 4 H), 2.96-3.07 (m, 4 H), 4.19 (s,
2 H), 4.25 (s, 2 H), 7.11 (d, J ) 9.4 Hz, 1 H), 7.45-7.62 (m, 6
H), 7.95 (s, 1 H), 8.09 (s, 1 H), 9.12 (s, 1 H) ppm; UV-vis (H2O,
pH ) 6.0) λ (ꢀ) 223 (35 000), 243 (62 000), 312 (44 000), 327
(55 000), 345 (22 000) nm (M-1 cm-1); fluorescence (H2O, pH
) 6.0, λexc ) 327 nm) λem 425, 444, 472 nm. Anal. Calcd for
C28H30N4‚3.5HCl‚2.2H2O: C, 57.02; H, 6.48; N, 9.50. Found:
C, 57.01; H, 6.43; N, 8.96.
H), 4.79 (s, 8 H), 8.40 (d, J ) 9 Hz, 4 H, H(3/10)), 8.44 (d, J ) 9
Hz, 4 H, H(4/9)), 8.72 (s, 4 H, H(1/12)), 8.77 (s, 4 H, H(6/7)), 10.60
(s, 4 H, H(13/14)) ppm; UV-vis (H2O, pH ) 6.0) λ (ꢀ) 245
(135 000), 299 (62 000), 324 (46 000) nm (M-1 cm-1); fluores-
cence (H2O, pH ) 6.0, λexc ) 324 nm) λem 409, 434, 469 nm;
MS (Electrospray, MeOH/H2O 1/1) m/z 815.25 ([C52H50N10
+
H]+), 407.5 ([C52H50N10 + 2H]2+/2). Anal. Calcd for C52H50
-
N10‚9HCl‚2.5H2O: C, 52.56; H, 5.43; N, 11.79. Found: C,
52.55; H, 5.48; N, 11.26.
3,10-Bis((n -p r op yla m in o)m e t h yl)d ib e n zo[b,j][1,10]-
p h en a n th r olin e (11a ). n-Propylamine (330 mg, 5.57 mmol)
was added to a clear suspension of 6a (75 mg, 0.223 mmol) in
4/1 CH2Cl2/MeOH (150 mL) at room temperature. The solu-
tion was stirred for 2 h, and the solvents were distilled off.
The crude diimine was dissolved in methanol (20 mL) and
cooled to 0 °C. NaBH4 (21 mg, 0.557 mmol) was added, and
the solution was stirred at 0 °C for 2 h and at room temper-
ature for 30 min. The solvents were distilled off, water was
added, and the product was extracted with dichloromethane.
The organic layer was dried over Na2SO4 and evaporated. The
1 N HCl was added, and 11a ,HCl was precipitated with THF.
It was recrystallized from 1 N HCl and ethanol, yielding 54
mg (43%) of an orange powder: salt decomposition g 150 °C;
1H NMR (D2O, pH ) 2.1) δ 0.88 (t, 6 H), 1.60-1.71 (m, 4 H),
3,10-Bis[[(3-(d im et h yla m in o)p r op yl)a m in o]m et h yl]-
d iben zo[b,j][1,10]p h en a n th r olin e (12). 12 was obtained in
the same manner as above for 11a , from 3-(dimethylamino)-
propylamine and 6a : orange yellow powder (43%); salt de-
1
composition g 150 °C; H NMR (D2O, pH ) 3.2) δ 2.13 (m, 4
H), 2.81 (s, 12 H), 3.12-3.21 (m, 8 H), 4.40 (s, 4 H), 7.48 (s, 2
H, H(6/7)), 7.78 (d, J ) 9 Hz, 2 H, H(2/11)), 8.02 (s, 2 H, H(4/9)),
8.11 (d, J ) 9 Hz, 2 H, H(1/12)), 8.64 (s, 2 H, H(5/8)) ppm; 13C
NMR (D2O, pH ) 3.2) δ 21.5, 43.2, 44.6, 51.1, 54.6, 126.7,
127.6, 127.8, 128.2, 130.6, 130.8, 133.1, 139.8, 143.2, 144.3
ppm. Anal. Calcd for (C32H40N6‚5HCl‚4.4H2O): C, 49.90; H,
7.04; N, 10.91. Found: C, 49.87; H, 6.47; N, 10.58.
J O970496B