Dinuclear zinc(II) double-helicates of homochirally substituted bis(dipyrromethene)s

Article abstract of DOI:10.1021/jo051727e

A series of bis(dipyrromethene)s substituted with aromatic amide and aliphatic ester homochiral auxiliaries have been prepared and complexed with zinc(II) ions to form double-helical dinuclear complexes. CD analysis of the crude complexes revealed that th

Full text of DOI:10.1021/jo051727e

Dinuclear Zinc(II) Double-Helicates of Homochirally Substituted
Bis(dipyrromethene)s
Tabitha E. Wood,† Avena C. Ross,† Nathan D. Dalgleish,† Erin D. Power,† Alison Thompson,*,†
Xiaoming Chen,‡ and Yoshio Okamoto‡
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia B3H 4J3, Canada,
Ecotopia Science Institute, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan
alison.thompson@dal.ca
Received August 15, 2005
A series of bis(dipyrromethene)s substituted with aromatic amide and aliphatic ester homochiral
auxiliaries have been prepared and complexed with zinc(II) ions to form double-helical dinuclear
complexes. CD analysis of the crude complexes revealed that the helicates formed in a diastereo-
selective manner. The helicates have been resolved into their constituent M and P helices by HPLC,
indicating that the helical sense of the complexes is stable to racemization.
Introduction
Self-assembling1 helicates have consistently been of
interest in the field of supramolecular science.2 As an
example, oligopyridines, as well as 2,2′-bipyridyl (bipy),
1,10-phenanthroline (phen), 2,2′:6′,2′′-terpyridyl (terpy),
and 2,2′:6′,2′′:6′′:2′′′-quaterpyridine derivatives, have
proven very popular ligands for the synthesis of heli-
cates.3 Other ligands that are useful in self-assembly
processes include the fully conjugated bipyrrolic class of
molecules known as dipyrromethenes. These molecules,
an example of which is shown in Figure 1, are, structur-
ally, half of a porphyrin ring. It is for this reason that
they were originally prepared as synthetic precursors to
porphyrins and other cyclic tetrapyrroles.4 Dipyrro-
methenes are generally stored and handled as their
hydrobromide salts, although those that bear electron-
FIGURE 1. Structural comparison of a porphyrin and a
dipyrromethene.
withdrawing substituents in the 5-position are stable in
their free-base form.5
It was soon discovered that deprotonated monoanionic
dipyrromethenes form complexes with a wide variety of
metal ions.6 These metal complexes were originally of
great interest as efficient templates in the synthesis of
cyclic tetrapyrroles4 and have been isolated as byproducts
of the Rothemund synthesis of arylporphyrins.7,8 There-
after, the significance of dipyrromethenes in the study
of coordination chemistry became apparent. The steric
† Dalhousie University.
‡ Nagoya University.
(1) Lehn, J.-M. Supramolecular Chemistry; VCH Verlagsgesell-
schaft: New York, 1995.
(5) Bru¨ckner, C.; Karunaratne, V.; Rettig, S. J.; Dolphin, D. Can.
J. Chem. 1996, 74, 2182-2193.
(2) Albrecht, M. Chem. Rev. 2001, 101, 3457-3497.
(3) Constable, E. C. Polynuclear Transition Metal Helicates. In
Templating, Self-Assembly, and Self-Organization; Elsevier Science,
Ltd.: Exeter, 1996; Vol. 9, Chapter 6.
(6) Fischer, H.; Schubert, M. Ber. 1924, 57B, 610-7.
(7) Badger, G. M.; Jones, R. A.; Laslett, R. L. Aust. J. Chem. 1964,
17, 1028-35.
(4) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pig-
ments; Springer-Verlag: New York, 1989.
(8) Hill, C. L.; Williamson, M. M. J. Chem. Soc., Chem. Commun.
1985, 1228-9.
10.1021/jo051727e CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/01/2005
J. Org. Chem. 2005, 70, 9967-9974
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Wood et al.
ation.20-23 A recent publication reports the synthesis of
non-symmetrical 2,3′-bis(dipyrromethene)s and their
zinc(II) complexation products.24 The first example of a
2,2′-bis(dipyrromethene) forming a double helicate with
metal ions was reported for cobalt(II) in 1966,25 although
X-ray crystal structure data was not obtained until 1980
for a zinc(II) complex of a similar ligand.26 The metal-
to-ligand ratio of the complexation product of 2,2′-bis-
(dipyrromethene)s is highly dependent upon the struc-
ture of the ligand and the solvent that is employed for
the complexation reaction. For reaction with the same
ligand, cobalt(II) has been shown to form 1:1 monomeric
helical complexes in ethanol and 2:2 dimeric helicates
when the reaction is conducted in methanol.25 Similar
products were obtained for the products of copper(II)
complexation of a 2,2′-bis(dipyrromethene) in which the
two dipyrromethene units were directly attached at the
2,2′-position without a spacer.27 In general, those metal
ions for which a square planar coordination geometry is
preferred, such as nickel(II), copper(II), and palla-
dium(II), yield monomeric helical complexes with dipyrro-
methenes,28-30 while metal ions for which tetrahedral
geometry is the preferred mode of coordination, such as
cobalt(II) and zinc(II), yield dinuclear dimeric double
helicates.25,26,29-31
Interest in bis(dipyrromethene) helicates for use in
supramolecular chemistry was shown in 1998 with the
report of a series of cobalt(II) and zinc(II) complexes in
which the length of the 2,2′-spacer was varied.32 This was
followed by reports of 3,3′-bis(dipyrromethene)s which
demonstrated that the metal-to-ligand ratio in the com-
plexation products of these ligands was highly dependent
upon the length of the 3,3′-spacer.21,23 Monomeric cobalt-
(II) and zinc(II) complexes were formed when the spacer
was six or more carbons in length, dimeric when the
spacer was one to three carbons in length, and trimeric,23
with a metal-to-ligand ratio of 3:3, when there was no
spacer and the two dipyrromethene units were directly
bonded to each other. Several other reports regarding the
synthesis and structure of dinuclear zinc(II) complexes,33-35
nickel(II) complexes,36 and cobalt(II) complexes35 of 3,3′-
FIGURE 2. Structures of 2,2′- and 3,3′-bis(dipyrromethene)s.
interactions between 1,9-substituents of two dipyr-
romethenes coordinated to the same metal, even those
as small as hydrogens, of the dipyrromethenes9 were
found to distort the geometry of coordination about the
metal ions. As such, even those metal(II) ions for which
square planarity is usually the preferred geometry adopt
pseudotetrahedral coordination geometry with dipyr-
romethene ligands.10,11 An advantage to the use of
dipyrromethenes is that their metal complexes often do
not require counterions since the ligands are charged,
therefore resulting in less disorder in their crystal
structures and the ability to be purified by standard
chromatographic methods. Although dipyrromethenes
are known to readily form complexes with many different
metal ions under mild conditions, contemporarily the
most common complexes are those of boron difluoride.
Dipyrromethene complexes of this type are known as
bodipy dyes. Fluorescent bodipy dyes have found exten-
sive use in optical12 and biological applications due to
their high absorption and emission, stability, pH inde-
pendence, highly tunable optical properties, and high
functionalizability and because many are commercially
available.13 Recent research has shown that the fluores-
cence quantum efficiencies of transition-metal complexes
of dipyrromethenes, which under similar conditions are
significantly lower than those of bodipy dyes, can be made
higher by the judicious choice of subsituents.14
Improved procedures for the synthesis of dipyr-
romethenes bearing aryl substituents in the 5-position5,15
have created a renewal of interest in dipyrromethene
metal complex chemistry.16-18 Bis(dipyrromethene)s pro-
vide access to a variety of metal complex architectures,
including helices and double helices. As shown in Figure
2, the two dipyrromethene units of bis(dipyrromethene)s
may be connected through the 2,2′- or the 3,3′-positions.
Linkage through the 2,2′-positions by a methylene group
is historically the most common connection due to the
use of these structures in the syntheses of corroles.19
More recently, linkage through the 3,3′-positions has
become more common, as such skeletons are facile to
prepare and give interesting structures upon complex-
(20) Paine, J. B., III; Dolphin, D. Can. J. Chem. 1978, 56, 1710-
12.
(21) Thompson, A.; Rettig, S. J.; Dolphin, D. Chem. Commun. 1999,
631-632.
(22) Thompson, A.; Dolphin, D. Org. Lett. 2000, 2, 1315-1318.
(23) Thompson, A.; Dolphin, D. J. Org. Chem. 2000, 65, 7870-7877.
(24) Yang, L.; Zhang, Y.; Chen, Q.; Ma, J. S. Monatsh. Chem. 2004,
135, 223-229.
(25) Dolphin, D.; Harris, R. L. N.; Huppatz, J. L.; Johnson, A. W.;
Kay, I. T. J. Chem. Soc. C 1966, 30-40.
(26) Sheldrick, W. S.; Engel, J. J. Chem. Soc., Chem. Commun. 1980,
5-6.
(9) Porter, C. R. J. Chem. Soc. 1938, 368-72.
(10) Elder, M.; Penfold, B. R. J. Chem. Soc. A 1969, 2556-9.
(11) Cotton, F. A.; DeBoer, B. G.; Pipal, J. R. Inorg. Chem. 1970, 9,
783-8.
(12) Shah, M.; Thangaraj, K.; Soong, M. L.; Wolford, L.; Boyer, J.
H.; Politzer, I. R.; Pavlopoulos, T. G. Heteroatom. Chem. 1990, 1, 389-
99.
(27) Dolphin, D.; Harris, R. L. N.; Huppatz, J. L.; Johnson, A. W.;
Kay, I. T.; Leng, J. J. Chem. Soc. C 1966, 98-106.
(28) Johnson, A. W.; Price, R. J. Chem. Soc. 1960, 1649-1653.
(29) Murakami, Y.; Kohno, Y.; Matsuda, Y. Inorg. Chim. Acta 1969,
3, 671-5.
(30) Murakami, Y.; Matsuda, Y.; Kanaoka, Y. Bull. Chem. Soc. Jpn.
1971, 44, 409-15.
(13) Haugland, R. P. Handbook of Fluorescent Probes and Research
Chemicals, 9th ed.; Molecular Probes Inc.: Eugene, OR, 2002.
(14) Sutton, J. M.; Rogerson, E.; Wilson, C. J.; Sparke, A. E.;
Archibald, S. J.; Boyle, R. W. Chem. Commun. 2004, 1328-1329.
(15) Wagner, R. W.; Lindsey, J. S. Pure Appl. Chem. 1996, 68, 1373-
1380.
(31) Murakami, Y.; Matsuda, Y.; Kobayashi, S. J. Chem. Soc., Dalton
Trans. 1973, 1734-7.
(32) Zhang, Y.; Thompson, A.; Rettig, S. J.; Dolphin, D. J. Am. Chem.
Soc. 1998, 120, 13537-13538.
(33) Zhang, Y.; Ma, J. S. Org. Prep. Proced. Int. 2001, 33, 81-86.
(34) Zhang, Y.; Wang, Z.; Yan, C.; Li, G.; Ma, J. Tetrahedron Lett.
2000, 41, 7717-7721.
(16) Bru¨ckner, C.; Zhang, Y.; Rettig, S. J.; Dolphin, D. Inorg. Chim.
Acta 1997, 263 (1-2), 279-286.
(17) Halper, S. R.; Cohen, S. M. Chem. Eur. J. 2003, 9, 4661-4669.
(18) Cohen, S. M.; Halper, S. R. Inorg. Chim. Acta 2002, 341, 12-
16.
(35) Yang, L.; Zhang, Y.; Yang, G.; Chen, Q.; Ma, J. S. Dyes Pigments
2004, 62, 27-33.
(36) Shan, X.; Yang, L.; Li, W.; Chen, Q.; Wang, Z.; Hu, J.; Ma, J.
S. J. Chem. Crystallogr. 2004, 34, 433-439.
(19) Johnson, A. W.; Kay, I. T. J. Chem. Soc. 1965, 1620-9.
9968 J. Org. Chem., Vol. 70, No. 24, 2005

Complexation of Homochiral Bis(dipyrromethene)s
FIGURE 3. Homochirally substituted bis(dipyrromethene) zinc(II) helicates.
FIGURE 4. Disconnection strategy for the synthesis of homochirally substituted bis(dipyrromethene)s.
bis(dipyrromethene)s have been published. Helical 3,3′-
diastereoselectively.38 The helicates were shown to be
bis(dipyrromethene) complexes of zinc(II) have since been
sufficiently stereochemically stable to allow isolation of
the M and P helices by chiral HPLC. In this paper, the
diastereoselective complexation of a range of bis(dipyr-
romethene) ligands homochirally appended with amides
and esters is demonstrated, and the influence of the
chiral auxiliary is discussed.
1
studied by H NMR spectroscopy and shown to form as
a racemic mixture of M and P helices.22 A resolution of
the M and P helices of a 1:1 nickel(II) 2,2′-bis(dipyr-
romethene) complex was achieved in 2001 by MPLC
using a chiral column.37 Circular dichroism (CD) analysis
showed that the helical enantiomers did not racemize,
even with prolonged heating.37
Results and Discussion
BINOL- and tartrate-linked bis(dipyrromethene) ligands
give excellent diastereoselectivity for the formation of
mononuclear helicates.41 In a previously published report,
it was demonstrated that dinuclear, double-stranded
helical zinc(II) complexes of homochirally substituted
3,3′-bis(dipyrromethene)s 1a and 1b (Figure 3) form
Figure 4 shows a disconnection strategy for the syn-
thesis of bis(dipyrromethene)s substituted with terminal
homochiral amides or esters. This strategy allows for a
range of homochiral moieties to be incorporated, as well
as for varying the length of the spacer between the
dipyrromethene unit and the auxiliary. It was anticipated
that access to such a variety of skeletons would enable
the scope of the effect of the auxiliary type and position
upon the diastereoselectivity of complexation to be fully
studied.
Although the molecule A in Figure 4 is symmetric, each
dipyrromethene unit therein is asymmetric. The synthe-
sis of asymmetric dipyrromethenes is most effectively
accomplished by the condensation reaction of (appropri-
(37) Bro¨ring, M.; Brandt, C. D.; Lex, J.; Humpf, H.-U.; Bley-Escrich,
J.; Gisselbrecht, J.-P. Eur. J. Inorg. Chem. 2001, 2549-2556.
(38) Wood, T. E.; Dalgleish, N. D.; Power, E. D.; Thompson, A.; Chen,
X.; Okamoto, Y. J. Am. Chem. Soc. 2005, 127, 5740-5741.
(39) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chem.
Soc. 1960, 82, 4384-4389.
(40) Johnson, A. W.; Markham, E.; Price, R.; Shaw, K. B. J. Chem.
Soc. 1958, 4254-4257.
(41) Al-Sheikh-Ali, A.; Cameron, K. S.; Robertson, K. N.; Cameron,
T. S.; Thompson, A. Org. Lett. 2005, 7, 4773-4775.
J. Org. Chem, Vol. 70, No. 24, 2005 9969

Wood et al.
SCHEME 1. Synthesis of the Homochiral Substituted Pyrrole Amides and Esters
TABLE 1. Yields for the Synthesis of Pyrrole
Derivatives 6a-l
ately substituted) 2-formylpyrroles (B) with pyrroles that
are unsubstituted in the R-position. These R-unsubsti-
tuted pyrroles, also known as R-free, can be prepared in
situ by decarboxylation of the corresponding R-carboxylic
acid derivative, which in turn is easily prepared by
hydrogenolysis of the benzyl ester derivative (C), syn-
thesized on large scales via Knorr-type reactions. The bis-
(dipyrromethene) ligands can be formed by coupling 2
equiv of the R-free derivative of homochirally substituted
pyrroles with 1 equiv of a diformyldipyrromethane.39 The
homochiral substituents can be incorporated into the
pyrrole by the use of amide and ester derivatives of a
pyrrole carboxylic acid (D) and homochiral amines and
esters (E).
The homochiral substituents were incorporated into
the bis(dipyrromethene)s early in the synthesis by at-
taching the chiral auxiliaries to 2-benzyl carboxylate
pyrroles that would later be transformed into R-free
pyrroles for incorporation into dipyrromethenes. Chemose-
lective hydrolysis of the methyl ester functional group
in benzyl 4-(2-methoxycarbonylethyl)-3,5-dimethylpyr-
role-2-carboxylate40 (2) using aqueous lithium hydroxide
provided benzyl 3,5-dimethyl-4-(propanoic acid)pyrrole-
2-carboxylate (4)38 (Scheme 1). Similarly, benzyl 4-(etha-
noic acid)-3,5-dimethylpyrrole-2-carboxylate (5) was pre-
pared by hydrolysis of benzyl 4-(methoxycarbonylmethyl)-
3,5-dimethylpyrrole-2-carboxylate (3).41
a 6a,c,e,g,i have (S) absolute stereochemistry. b Averaged yields
for the two enantiomers.
The carboxylic acid functionality of pyrroles 4 and 5
provided excellent handles for the incorporation of ho-
mochiral auxiliaries through the synthesis of chiral
amides and esters. Amides were prepared by the coupling
of optically pure chiral amines with 4 or 5 with O-ben-
zotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluo-
rophosphate (HBTU) or a combination of N-(3-dimethy-
laminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC‚
HCl) and 1-hydroxybenzotriazol hydrate (HOBT). Like-
wise, esters were prepared by the coupling of optically
pure chiral alcohols. For coupling reactions involving 4,
dichloromethane was used as a solvent and HBTU as a
coupling reagent, providing high yields of the desired
products. The pyrrole carboxylic acid 5 is sparingly
soluble in dichloromethane, so tetrahydrofuran was used
as the solvent for coupling reactions of this compound.
For the preparation of amides from 5, HBTU was utilized
as the coupling reagent while for the preparation of esters
from 5 EDC‚HCl/HOBT provided higher product yields.
In preliminary work, N,N′-dicyclohexylcarbodiimide (DCC)
was used as the coupling reagent in the synthesis of
amides 6e-h. However, unsatisfactory results were
obtained, and the N-acylurea side product 7 (Figure 5)
dominated.42 The products 6a-l were obtained following
workup suited to removal of the coupling reagent and
FIGURE 5. N-Acylurea side product obtained from the use
of DCC.
subsequent column chromatography. The yields of prod-
ucts 6a-l are listed in Table 1.
The bis(dipyrromethene)s ligands were prepared in two
synthetic steps from the homochiral auxiliary-bearing
pyrroles 6a-l. Hydrogenolysis of the benzyl group from
compounds 6a-l at atmospheric pressure using pal-
ladium on carbon as a catalyst provided the R-carboxylic
acid required for preparation of the dipyrromethene
(Scheme 2). Monitoring of the reactions by TLC was
necessary so as to avoid hydrogenolysis of the benzyl
substituents of the aliphatic amides or esters, rather than
just the pyrrole R-benzyl ester as required. In the case
of 6k, hydrogenation of the pentene substituent occurred
in addition to the hydrogenolysis of the pyrrole R-benzyl
ester. The bis(dipyrromethene)s were synthesized by
coupling the homochiral amide or ester pyrrole-2-car-
(42) Klausner, Y. S.; Bodanszky, M. Synthesis 1974, 549-559.
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Complexation of Homochiral Bis(dipyrromethene)s
SCHEME 2. Synthesis of the Bis(dipyrromethene) Hydrobromide Salts Bearing Homochiral Substituents
SCHEME 3. Synthesis of the Zinc(II) Bis(dipyrromethene) Helicates Bearing Homochiral Substituents
boxylic acid with 2,2′,4,4′-tetramethyl-5,5′-diformyl-3,3′-
dipyrromethane33 (8) in the presence of hydrobromic acid
yielding the hydrobromide salts of the homochirally
substituted bis(dipyrromethene)s (9a-l). Salts 9a-l were
isolated by precipitation either during the reaction or
from minimal dichloromethane by the addition of diethyl
ether or hexanes, followed by filtration. The poor solubil-
ity of the amide-containing ligands was overcome by the
incorporation of a third substituent on the amide nitrogen
center, as 9c and 9d were much more soluble than 9a
and 9b in the solvents tested. The propanoic derivatives
9a,b were generally more soluble than their ethanoic
counterparts 9e-h. The ester-containing ligands 9i-l
were all quite soluble in conventional solvents. However,
it should be noted that complete dissolution of the bis-
(dipyrromethene) hydrobromide salt is not necessary to
effect complexation of the ligand to zinc(II) ions.
The preparation of zinc(II) complexes 10a-l was
accomplished by the addition of a solution of excess zinc
acetate and sodium acetate in methanol to a solution of
the ligand in chloroform (Scheme 3) using a procedure
modified from literature.23 Those ligands that were only
sparingly soluble in chloroform and were suspensions
rather than solutions in chloroform at the beginning of
the reaction were seen to dissolve as complexation
proceeded. The formation of zinc(II) complexes of dipyr-
romethenes is easily monitored by analysis of the visible
absorbance spectrum of the reaction mixture. Upon
complexation the wavelength of maximum absorbance
(λmax) generally undergoes a bathochromic shift of ap-
proximately 20 nm. This shift of λmax is usually observable
by visual inspection, with the reaction mixture changing
color from orange to fuscia over the course of the
complexation reaction. The diastereomeric helicate prod-
ucts are obtained in good yield as a mixture through
routine workup involving extraction and precipitation
from minimal dichloromethane by the addition of diethyl
ether. The zinc complexes are generally stable to silica
flash chromatography and this technique can be used for
purification, if necessary, although separation of M and
P helical diastereoisomers was not achieved using this
procedure. However, some decomposition was observed
for compounds 1a,b, 10a,b, and 10e-h during attempted
separations of diastereoisomers using silica chromatog-
raphy. As 1a,b, 10a,b, and 10e-h are secondary amides
this observed decomposition suggests that the decompo-
sition is facilitated by primary amides. Deuterium ex-
change was observed by 1H NMR spectroscopy for these
amide hydrogens upon the addition of deuterated water
on the time scale of less than 24 h and also in deuterated
chloroform in less than 4 days.
Mass spectrometry confirmed the formation of di-
nuclear complexes with the stoichiometry M2L2, rather
than monomers or oligomers. The presence of two sources
of chirality, one fixed (the auxiliary) and one variable (the
helix), gives rise to two possible diastereoisomers. Cir-
cular dichroism (CD) spectra were recorded for each
diastereomeric mixture of helicates 10a-l. Every sample
exhibits a measurable ellipticity, which indicates that
there exists an excess of one diastereoisomer over the
other in the mixtures. As anticipated, the ellipticities are
opposite for helicates resulting from enantiomeric ligands.
Since the absolute stereochemistry of the auxiliary is
fixed, the diastereomeric excess must arise from the
preferential generation of one helical sense over the other
in the complexation process. The activity observed in the
CD experiments arises from πfπ* transitions in the
dipyrromethene unit of the ligand.43 CD activity from
induced exciton coupling of a dipyrromethene unit with
an aromatic ring of the homochiral amide substituents
on the zinc(II) bis(dipyrromethene) helicate has been
ruled out by previous studies.38 Chiral HPLC44 analysis
has been performed upon several of these samples (10a-
d). Similar to the analysis of compounds 1a and 1b, these
samples displayed two major peaks monitored at 534 nm.
(43) Murakami, Y.; Sakata, K. Inorg. Chim. Acta 1968, 2, 273-279.
(44) Kubota, T.; Yamamoto, C.; Okamoto, Y. J. Polym. Sci., Part A:
Polym. Chem. 2003, 41, 3703-3712.
J. Org. Chem, Vol. 70, No. 24, 2005 9971

Wood et al.
FIGURE 6. (a) Chiral HPLC resolution of 10a; (b) CD spectra of the resolved M (I) and P (II) helices of 10a.
FIGURE 7. CD spectra of equimolar solutions of the diastereomeric mixtures for 10a and 10g.
CD spectra were recorded for the isolated contents of
these two major peaks from each HPLC resolution. These
resolved compounds displayed opposite and approxi-
mately equal CD spectra, supporting their identification
as the resolved M and P helicates. The chiral HPLC
elution profile and the CD spectra of the resolved helices
of 10a are shown in Figure 6. Isomers that show a
positive Cotton effect at the lower wavelength (∼470 nm)
and a negative Cotton effect with exciton coupling at the
higher wavelength (∼520 nm) are assigned as the M helix
and those with an opposite CD spectrum as the P helix.45
Thus, isomer I in Figure 6 was identified as the M helix,
and II the P helix, of 10a. Our work with BINOL-linked
bis(dipyrromethene) complexes that form monomeric
helicates has confirmed this assignment via X-ray crys-
tallography.41
The generation and isolation of single helicates of
dipyrromethene complexes is contingent upon the ster-
eochemical stability of the helices. Disassociation of the
metal complexes and the resulting scrambling of ligands
is a mechanism by which the chirality of the helical sense
might be racemized if the bis(dipyrromethene)s are labile
on the zinc(II) centers. To investigate the stability of the
helicity established during the formation of these com-
plexes, an equimolar solution of two different zinc heli-
cates (1b and 10d) in toluene was heated to reflux for
24 h, and alternately, an equimolar solution of the
helicates in dichloromethane was stirred at room tem-
perature for 24 h. Analysis of the reaction mixtures using
MALDI-MS revealed no apparent ligand exchange be-
tween the two compounds, as observed by the lack of any
compound of intermediate mass, as would be present if
ligand scrambling had occurred. The mass spectrum of
the reaction mixture showed only peaks associated with
the two starting zinc helicates (Supporting Information).
This study suggests that the bis(dipyrromethene) ligands
are non-labile on zinc(II) metal centers under neutral
conditions. Racemization of the chiral sense of the helices
might also occur by a mechanism of inversion of the
stereochemistry about the metal ion center. Further
investigations involving time-dependent CD studies will
be conducted to further investigate the non-inversion of
stereochemistry at the chiral metal center.
As can be seen by comparison of the CD spectra of the
diastereomeric mixtures of 10a and 10g, where only the
length of the pyrrole-auxiliary spacer changes (Figure 7),
the magnitudes of the circular dichroisms are similar.
This demonstrates that, somewhat surprisingly, the
length of the spacer between the dipyrromethene unit
and the chiral auxiliary does not significantly affect the
diastereoselectivity of the complexation reaction. By
comparing the molar ellipticity values of their diastere-
omeric mixtures, the zinc(II) complexes of the ester bis-
(dipyrromethene) derivatives (10i-l) likely formed with
similar diastereoselectivity to the amide derivatives.
Again, this is somewhat unexpected as free rotation about
the O-carbonyl bond, and thus greater number of degrees
of freedom for the esters by which to minimize steric
crowding, was predicted to induce lower stereoselectivity
than the amides which show a slow rotation as evidenced
by the diastereotopic relationship between the methylene
1
protons of the ethanoate and propanoate linkers in H
NMR spectra of these complexes.
In considering both the spacer length and the func-
tionality of the auxiliary, it is apparent from NMR spec-
(45) Boiadjiev, S. E.; Lightner, D. A. Tetrahedron: Asymmetry 1999,
10, 2535-2550.
9972 J. Org. Chem., Vol. 70, No. 24, 2005

Complexation of Homochiral Bis(dipyrromethene)s
resulting solution was stirred, and after 30 s a light pink solid
began to form. At this time, additional dry dichloromethane
(20 mL) was added, followed by O-(benzotriazol-1-yl)-N,N,N′,N′-
tetramethyluronium hexafluorophosphate (HBTU) (2.5 g, 6.6
mmol). The mixture stirred, eventually warming to room
temperature, for 2 days. The reaction mixture was then
filtered, concentrated, washed twice with 5% (w/vol) aqueous
hydrochloric acid solution, washed with brine, and concen-
trated by rotary evaporation. Purification by chromatography
using silica and 30% (v/v) ethyl acetate in hexanes as the
eluent gave the product as a white solid (2.2 g, 72%) (sol:
chloroform, methanol, dimethyl sulfoxide; sp. sol: dichlo-
romethane, acetone, ethyl acetate, ethanol; insol: water,
diethyl ether, hexanes): Rf 0.28 (silica, 40% ethyl acetate 60%
hexanes); mp 189-190 °C; 1H NMR: δ (250 MHz, CDCl3) 1.58
(3H, d, J ) 7.0 Hz), 2.06 (3H, s), 2.25 (3H, s), 2.27 (2H, t, J )
7.3 Hz), 2.72 (2H, t, J ) 7.0 Hz), 5.29 (2H, s), 5.50 (1H, d, J )
7.6 Hz), 5.82-5.93 (1H, m), 7.29-7.51 (9H, m), 7.75 (1H, d, J
) 7.9 Hz), 7.83 (1H, d, J ) 8.1 Hz), 8.03 (1H, d, J ) 7.3 Hz),
7.97 (1H, br s); 13C{1H} NMR δ (126 MHz, CDCl3) 10.9, 11.6,
20.4, 21.1, 37.7, 44.9, 65.7, 116.9, 120.6, 122.7, 123.6, 125.4,
126.0, 126.7, 128.3, 128.5, 128.8, 129.0, 130.5, 131.2, 134.1,
136.8, 138.6, 162.0, 171.4; EI-HRMS calcd 454.2256 for
C29H30N2O3, found 454.2266 (6a) and 454.2243 (6b).
troscopy that low diastereoselectivities are obtained with
the skeletons discussed herein and so the differences in
stereochemical induction for the various substituents are
small. The modest diastereoselectivity observed in the
synthesis of zinc helicates 10a-d show that the terminal
homochiral auxiliaries are too removed from the metal
center to induce efficient stereoselectivity during the
formation of the helicate. Nevertheless, the CD activity
observed for these reaction mixtures was the first un-
equivocal evidence that stereochemical induction was
feasible. Isolation of the M and P helices of compounds
10a-d show that the helical chirality of zinc(II) com-
plexes of bis(dipyrromethene)s is stable. Having estab-
lished that induction is feasible, current work involves
the development of increased stereoselectivity of bis-
(dipyrromethene) helicate formation by the incorporation
of homochiral auxiliaries, such as optically pure binol and
dimethyltartrate as template spacers joining two dipyr-
romethene units.41
Conclusions
Benzyl 3,5-Dimethyl-4-[2-(1,3-dicyclohexylureido)-2-
oxoethyl]-1H-pyrrole-2-carboxylate (7): (sol: chloroform,
methanol; sp. sol: dichloromethane, acetone; insol: water,
diethyl ether, hexanes); Rf 0.79 (silica, 60% ethyl acetate 40%
hexanes); mp 156-159 °C; 1H NMR δ (500 MHz, CDCl3) 1.12-
1.37 (12H, m) 1.58-1.81 (4H, m), 1.92-1.95 (4H, m), 2.16 (3H,
s, Ar-CH3), 2.25 (3H, s), 3.53 (2H, s), 3.65-3.67 (1H, m), 3.93-
3.97 (1H, m), 5.28 (2H, s), 7.18 (1H, br s), 7.31-7.40 (5H, m),
9.06 (1H, br s); 13C{1H} NMR δ (126 MHz, CDCl3) 11.1, 11.8,
24.9, 25.5, 25.6, 26.5, 31.1, 32.1, 32.9, 49.9, 56.7, 65.6, 115.1,
117.0, 128.1, 128.2, 128.7, 131.7, 136.7, 154.2, 161.6, 172.5;
EI+ calcd 493.3 for C29H39N3O4, 516.3 (M + Na)+.
Similar to the previously reported compounds 1a and
1b, the formation of zinc(II) helical complexes of a series
of homochirally substituted bis(dipyrromethene)s (10a-
l) is diastereoselective. These Zn(II) dipyrromethene
helicates form diastereoselectivly due to the inclusion of
homochiral auxiliaries in the ligand. The auxiliaries are
attached through either ester or amide bonds, and the
retrosynthetic strategy allows for the incorporation of a
wide range of auxiliaries and homochiral spacers/linkers
through well-documented coupling and functional group
manipulation. With success in diastereoselectively form-
ing dipyrromethene helicates, the synthesis of dipyr-
romethenes bearing homochirality in close proximity to
the chiral metal centers is ongoing. The results presented
herein strongly suggest that the Zn(II) center is stere-
ochemically stable in dipyrromethene helicates, and this
unusual behavior46-48 is being further investigated for
dipyrromethenes with other connectivities. Currently,
conditions for HPLC separation of the M and P helices
for each of compounds 10e-l are being elucidated, after
which an extended study of the stereochemical stability
of bis(dipyrromethene) double-helicates with a variety of
metal ions will be conducted.
Bis{3-[(S or R)-2-(1-naphthylethylcarbamoyl)ethyl]-
2,2′,4,4′-tetramethyldipyrromethene} Hydrobromide Salt
(9a or 9b). To a mixture of benzyl 3,5-dimethyl-4-[(S)-2-(1-
naphthylethylcarbamoyl)ethyl]-1H-pyrrole-2-carboxylate (6a)
(to prepare 9a) or benzyl 3,5-dimethyl-4-[(R)-2-(1-naphthyl-
ethylcarbamoyl)ethyl]-1H-pyrrole-2-carboxylate (6b) (to pre-
pare 9b) (0.56 g, 1.24 mmol) and a catalytic amount of 10 mol
% palladium on activated carbon (0.011 g) in a 100 mL round-
bottom flask was added tetrahydrofuran (25 mL). Hydro-
genolysis of the benzyl ester was achieved using an enclosed
hydrogenation apparatus. After the mixture was purged with
hydrogen gas, the mixture was stirred for 16 h. The mixture
was then filtered through a plug of Celite to remove the
catalyst. The filtrate was collected in a 100 mL round-bottom
flask and diluted with methanol (5 mL). At this time, 2,2′,4,4′-
tetramethyl-5,5′-diformyl-3,3′-dipyrromethane (8) (0.16 g, 0.62
mmol) was added, followed by the addition of 48% (w/v)
hydrobromic acid (0.40 mL). The reaction immediately turned
from a light brown suspension to a very dark red homogeneous
solution. The reaction was stirred for 20 min, dried with
anhydrous sodium sulfate, filtered, and concentrated to a dark
red liquid by rotary evaporation. To this dark red liquid was
added just enough chloroform to form a homogeneous solution,
and then diethyl ether was added to give a precipitate, which
was collected by filtration and rinsed with more diethyl ether
to give the product as a dark orange powder (0.45 g, 71%)
(sol: methanol, dimethyl sulfoxide; sp. sol: chloroform, dichlo-
romethane, ethanol, acetone, ethyl acetate; insol: water,
diethyl ether, hexanes): mp >250 °C dec; 1H NMR δ (500 MHz,
DMSO-d6) 1.42 (6H, d, J ) 7.2 Hz), 2.23 (6H, s), 2.30 (6H, s),
2.34-2.36 (4H, t, J ) 6.9 Hz), 2.43 (6H, s), 2.46 (6H, s), 2.62-
2.72 (4H, m), 3.73 (2H, s), 5.62-5.68 (2H, m), 7.32-7.38 (4H,
m), 7.35 (2H, d, J ) 7.7 Hz), 7.46 (2H, t, J ) 7.5 Hz), 7.52
(2H, t, J ) 7.2 Hz), 7.75 (2H, d, J ) 8.2 Hz), 7.89 (2H, d, J )
7.7 Hz), 8.05 (2H, d, J ) 8.2 Hz), 8.41 (2H, d, J ) 7.7 Hz),
12.16 (2H, br s), 12.20 (2H, br s); 13C{1H} NMR δ (126 MHz,
Experimental Section
Benzyl 3,5-Dimethyl-4-[(S or R)-2-(1-naphthylethyl-
carbamoyl)ethyl]-1H-pyrrole-2-carboxylate (6a or 6b).
Under dry conditions and using nitrogen gas as an inert
atmosphere, benzyl 3,5-dimethyl-4-(propanoic acid)pyrrole-2-
carboxylate (4) (2.0 g, 6.6 mmol) was dissolved in dry dichlo-
romethane (50 mL) in a dry two-neck 250 mL round-bottom
flask with stirring. To this was added 4-(N,N′-dimethylamino)-
pyridine (DMAP) (0.81 g, 6.6 mmol). The resulting solution
was cooled to 0 °C by suspension in an ice bath. At this lowered
temperature, (S)-(-)-1-(1-naphthyl)-R-ethylamine (to prepare
6a) or (R)-(+)-1-(1-naphthyl)-R-ethylamine (to prepare 6b) (1.1
mL, 1.2 g, 6.7 mol) was added slowly dropwise by syringe. The
(46) Charbonniere, L. J.; Gilet, M.-F.; Bernauer, K.; Williams, A. F.
Chem. Commun. 1996, 39-40.
(47) Meyer, M.; Kersting, B.; Powers, R. E.; Raymond, K. N. Inorg.
Chem. 1997, 36, 5179-5191.
(48) Kra¨mer, R.; Lehn, J.-M.; De Cian, A.; Fischer, J. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 703-706.
J. Org. Chem, Vol. 70, No. 24, 2005 9973

Wood et al.
DMSO-d6) 10.4, 10.4, 13.4, 13.4, 19.3, 20.1, 22.1, 35.3, 44.4,
121.4, 122.6, 122.7, 123.6, 125.8, 126.6, 127.6, 128.6, 129.1,
130.7, 140.8, 142.9, 144.5, 152.4, 152.7, 155.2, 155.3, 170.6;
ESI+ found 863.5 (M - 2HBr)+ (9a) and 863.5 (M - 2HBr)+
(9b); λmax(CH2Cl2) 505 nm, 462 nm; ꢀ505(CH2Cl2) 2.37 × 107 L
7.85 (4H, m), 7.97-8.08 (4H, m); 13C{1H} NMR δ (126 MHz,
CDCl3) 21.0, 21.3, 22.9, 37.34, 44.7, 44.8, 121.0, 122.6, 122.6,
123.6, 125.4, 125.5, 125.6, 126.0, 126.7, 128.4, 128.9, 131.3,
134.1, 135.4, 137.3, 138.6, 155.5, 171.6; APCI+ found 1857.6
(M + 6H)+ λmax (95% CH3OH, 5% CH2Cl2) 525 nm, 478 nm;
mol-1 dm-1; [Θ]502(CH2Cl2) ) -30473 deg cm2 dmol-1
.
ꢀ525 (95% CH3OH, 5% CH2Cl2) 2.30 × 106 L mol-1 dm-1; [Θ]475
-
(95% CH3OH, 5% CH2Cl2) ) -153238 deg cm2 dmol-1, [Θ]527
Zinc(II) Di(bis{3-[(S)-2-(1-naphthylethylcarbamoyl)-
ethyl]-2,2′,4,4′-tetramethyldipyrromethene}) (10a). In a
50 mL round-bottom flask, bis{3-[(S)-2-(1-naphthylethylcar-
bamoyl)ethyl]-2,2′,4,4′-tetramethyldipyrromethene} hydrobro-
mide salt (9a) (0.11 g, 0.11 mmol) was combined with chloro-
form (5 mL). In a 10 mL Erlenmeyer flask were combined zinc
acetate dihydrate (0.12 g, 0.54 mmol), sodium acetate trihy-
drate (0.074 g, 0.54 mmol), and methanol (5 mL). The acetate
solution in methanol was added to the bis(dipyrromethene)
solution in chloroform via a pipet. The mixture was stirred
for 20 min. The resulting dark purple solution was washed
with distilled water, dried with sodium sulfate, filtered, and
placed on a rotary evaporator to concentrate. A minimal
amount of dichloromethane was added, followed by hexanes
to precipitate the product as a fuscia-colored powder (0.076 g,
75%) (sol: chloroform, dichloromethane; sp. sol: methanol,
ethanol, acetone, ethyl acetate; insol: water, diethyl ether,
hexanes): mp >250 °C dec; 1H NMR δ (250 MHz, CDCl3) 1.38
(12H, d, J ) 4.5 Hz), 1.48-1.55 (12H, m), 1.89 (12H, d, J )
7.0 Hz), 2.10 (12H, d, J ) 2.0 Hz), 2.13-2.28 (20H, m), 2.60-
2.69 (8H, m), 3.41 (4H, br s), 5.63-5.72 (4H, m), 5.77-5.90
(4H, m), 6.86 (4H, d, J ) 3.3 Hz), 7.31-7.54 (20H, m), 7.71-
) +386884 deg cm2 dmol-1, [Θ]540 ) -134389 deg cm2 dmol-1
.
Acknowledgment. Financial support for this re-
search was provided by the Natural Sciences and
Engineering Research Council (NSERC) of Canada, the
Canadian Foundation for Innovation, the Nova Scotia
Research and Innovation Trust, Dalhousie University,
and the Killam Trusts. We thank Jack Shyh-Jye Lan
(Dalhousie University) for his assistance in acquiring
some of the CD data.
Supporting Information Available: Synthetic proce-
dures and characterization data for 6c-l, 9c-l, and 10b-l,
conditions for HPLC resolutions of 10a-d, and the MALDI-
mass spectra for the 1b and 10d ligand scrambling experi-
ments. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO051727E
9974 J. Org. Chem., Vol. 70, No. 24, 2005