Novel carboxylated pyrrole- and carbazole-based monomers. Synthesis and electro-oxidation features

Article abstract of DOI:10.1021/jo061531u

(Chemical Equation Presented) Carboxylated pyrrole (Pyr, a index)- and carbazole (Cbz, b index)-containing monomers 6-7a/b and 9a/b have been readily synthesized from the monobenzyl ester of L-glutamic acid and triamine 2 using Clauson-Kaas and amide coup

Full text of DOI:10.1021/jo061531u

Novel Carboxylated Pyrrole- and Carbazole-Based Monomers.
Synthesis and Electro-Oxidation Features
Senthil Govindaraji, Philippe Nakache, Vered Marks, Zvika Pomerantz, Arie Zaban,* and
Jean-Paul Lellouche*
Department of Chemistry, Bar-Ilan UniVersity, 52900 Ramat-Gan, Israel
lellouj@mail.biu.ac.il
ReceiVed July 24, 2006
Carboxylated pyrrole (Pyr, a index)- and carbazole (Cbz, b index)-containing monomers 6-7a/b and
9a/b have been readily synthesized from the monobenzyl ester of L-glutamic acid and triamine 2 using
Clauson-Kaas and amide coupling reactions. In contrast to Pyr-containing compounds 6-7a, and 9a,
the three Cbz-containing monomers 6-7b, and 9b have been found electroactive and were successfully
electropolymerized on a Pt electrode resulting in the deposition of corresponding insoluble electrocon-
ducting polyCOOH polyCbz-films poly(6-7b) and poly(9b).
Conducting polymer-coated micrometer-sized electrodes found
multiple uses as effective biosensing transducers of variable sizes
and shapes. One challenging step toward highly performant
electrochemical devices remains the covalent/noncovalent mode
of attachment of biomolecules (proteins, antibodies, DNA
sequences, oligosaccharides) onto conductive substrates. Re-
cently, we have reported the successful electrogeneration of
amine-sensitive (polypentafluorophenyl ester) electrochemically
stable chiral poly(dicarbazole) conductive films on Au micro-
electrodes.1 Resulting ester-activated modified electrodes al-
lowed the nondenaturing covalent attachment of both glucose
and polyphenol oxidases toward corresponding biosensor con-
structs.2 Lately, dendrimeric structures that have preorganized
peripheral functionalities and size-determined internal cavities
enabled the successful development of numerous important
applications:3 degradable dendrimeric prodrugs in drug delivery,4
light-emitting diodes,5 and redox active systems.6
at the periphery of multivalent dendrimeric and nondendrimeric
organic cores is a potentially powerful approach toward new
taylored potential/current-sensitive conducting films. Such films
will build on the oxidative generation of periphery-localized
and multivalently accessible cation radicals enabling polymer
growth in a polydirectional manner. Very few examples of
conducting polymeric systems generated in such a way have
been reported so far.7,8 All of them were nonfunctional since
postpolymerization covalent grafting of biological probes was
impossible because of the lack of chemical functionalization.
For example, Majoral-Roncali and co-workers fabricated elec-
troconductive poly(bithiophene) films from phosphorus-contain-
ing dendritic cores decorated by peripheral nonfunctional 2,2′-
bithiophene units.7 Electroactive composite matrices possessing
a strong affinity for Pt2+ ions have been also synthesized from
the electrocopolymerization of nonfunctional thiophene-linked
poly(amido-amine) (PAMAM) dendrimers and 3-Me-thiophene.8
Other structurally resembling nonfunctional thiophene- and Pyr-
In this context, attachment of electroactive heterocyclic
species, such as pyrrole (Pyr), thiophene, carbazole (Cbz) units,
(4) (a) de Groot, F. M. H.; Albrecht, C.; Koekkoek, R.; Beusker, P. H.;
Scheeren, H. W. Angew. Chem., Int. Ed. 2003, 42, 4490-4494. (b) Amir,
R. J.; Pessah, N.; Shamis, M.; Shabat, D. Angew. Chem., Int. Ed. 2003, 42,
4494-4499.
(5) Furuta, P.; Brooks, J.; Thompson, M. E.; Fre´chet, J. M. J. J. Am.
Chem. Soc. 2003, 125, 13165-13172.
(6) Astruc, D.; Daniel, M. C.; Ruiz, J. Chem. Commun. 2004, 2637-
2649.
(7) Sebastian, R. -M.; Caminade, A. -M.; Majoral, J. -P.; Levillain, E.;
Huchet, L.; Roncali, J. Chem. Commun. 2000, 507-508.
(8) Alvarez, J.; Sun, L.; Crooks, R. M. Chem. Mater. 2002, 14, 3995-
4001.
(1) Pe´rie´, K.; Marks, R. S.; Szumerits, S.; Cosnier, S.; Lellouche, J.-P.
Tetrahedron Lett. 2000, 41, 3725-3729.
(2) (a) Cosnier, S.; Marks, R. S.; Lellouche, J.-P.; Pe´rie´, K.; Fologea,
D.; Szunerits, S. Electroanalysis 2000, 12, 1107-1112. (b) Cosnier, S.;
Szunerits, S; Marks, R. S.; Lellouche, J.-P.; Pe´rie´, K. J. Biochem. Biophys.
Methods 2001, 50, 65-77. (c) Cosnier, S.; Le Pellec, A.; Marks, R. S.;
Pe´rie´, K.; Lellouche, J.-P. Electrochem. Commun. 2003, 5, 973-977.
(3) (a) Fischer, M.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1999, 38, 884-
905. (b) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665-1688.
10.1021/jo061531u CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/25/2006
J. Org. Chem. 2006, 71, 9139-9143
9139

Govindaraji et al.
SCHEME 1. Synthesis of C2-/C3-symmetrical Pyr- and Cbz-Based Carboxylated Compounds 6-7a/b
based dendrimeric systems have been disclosed, but their elec-
trical/electro-oxidation properties were never described.9 Mc-
Carley and co-workers reported the intramolecular oligomerization
of nonfunctional Pyr-modified diaminobutane (DAB)-Pyrx (X
) 4, 8, and 16) dendrimers that were monolayered on a Au
electrode.10,11 Only adsorbed DAB-Pyr16 layers could be electro-
chemically oxidized causing intramolecular oligomerizations of
peripheral Pyr units. Accordingly, the capability of these mono-
meric multivalent electro-oxidizable species to grow conducting
polypyrrole-based films/matrices remained to be established.
Clearly, none of formerly described multivalent monomers
present outer pending oxidizable functionalities enabling the
postpolymerization covalent grafting of biomolecules onto
corresponding polymer-coated electrodes.
fact, six novel polycarboxylated homochiral monomers 6-7a/
b, and 9a/b (a and b indexes: Pyr- & Cbz-based series
respectively, Schemes 1 and 2) were readily synthesized from
both Pyr- and Cbz-derivatives of L-glutamic acid (S)-1a/b. For
the first time, polyCOOH functional and stable electroconduc-
tive polyCbz-films poly(6-7b) and poly(9b) have been pro-
duced by electropolymerization of corresponding carboxylated
Cbz-monomers on a Pt electrode. Therefore and in agreement
with former results,1,2 the postpolymerization covalent grafting
of biomolecules onto these fabricated conducting surfaces
(COOH-related activation chemistry) should allow the develop-
ment of numerous applications in the biosensing field for
example.
Polyfunctional compounds 6-7a/b presented four and six
electro-oxidizable decorating peripheral Pyr-/Cbz-units and
COOH groups. They included tunable acidic aromatic core
linkers modified by C2-/C3-symmetrization amidations (dicy-
clohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt)-
mediated and amine-acid chloride coupling key reactions,
convergent approach). On the other hand, compounds 9a/b were
produced by DCC/HOBt-mediated triamidations of triamine 2
using Pyr-/Cbz-containing compounds 1a/b. They disclosed
three Pyr-/Cbz-units and COOH groups.
Herein, we report our own studies relating to the straight-
forward electrosynthesis of novel polycarboxylated conducting
polyCbz-films from one unique carboxylated Cbz-containing
building block as new electro-oxidizable peripheral species. In
(9) (a) Deng, S.; Locklin, J.; Patton, D.; Baba, A.; Advincula, R. C. J.
Am. Chem. Soc. 2005, 127, 1744-1751. (b) Xia, C.; Fan, X.; Locklin, J.;
Advincula, R. C. Org. Lett. 2002, 4, 2067-2070. (c) Miller, L. L.; Kunugi,
Y.; Canavesi, A.; Rigaut, S.; Moorefield, C. N.; Newkome, G. R. Chem.
Mater. 1998, 10, 1751-1754. (d) Kim, K.-S.; Katsuraya, K.; Yachi, Y.;
Hatanaka, K.; Uryu, T. Sen’i Gakkaishi 2000, 56, 584-591.
(10) Noble, C. O., IV; McCarley, R. L. Org. Lett. 1999, 1, 1021-1023.
(11) Noble, C. O., IV; McCarley, R. L. J. Am. Chem Soc. 2000, 122,
6518-6519.
These modular synthetic approaches were found economical
in steps (3-4 steps maximum) mainly because of the use of
synthetically advanced chiral C2-symmetrical (S,S)-bis-Pyr-/
9140 J. Org. Chem., Vol. 71, No. 24, 2006

Carboxylated Pyrrole- and Carbazole-Based Monomers
SCHEME 2. Pyr/Cbz-Based Monomers 9a/b (One-Step Triamidation of Triamine 2) and 10b. Cation Radicals 11a/b Toward
Related Cycloadducts 12a/b
Cbz-building blocks 3a/b. Clearly, this chemical design should
allow a great chemical maneuverability at the core level for
future monomer developments.
b, 70/74% and 5a/b, 70/68%). Monomers 4a/b and 5a/b
presented four and six heterocyclic Pyr-/Cbz-units/Bn ester
functions, respectively. On the other hand, less complex
intermediates 8a/b possessing three Pyr-/Cbz-units and Bn ester
functions were prepared in one step from blocks 1a/b and
triamine 2 (Scheme 2).
Addition of anhydrous triethylamine was found necessary in
key step DCC/HOBt-promoted triamidations in order to proceed
beyond previously noticed 1,ω-diamidations (DCM, DCC/
HOBt, anhydrous Et3N, 20 °C, 5 h; 8a/b, 75/71%). Resulting
Pyr-/Cbz-based benzylated intermediates were thoroughly char-
acterized using high-field 1H-/13C NMR and low-/high-resolution
mass spectrometry analyses (Supporting Information).
Starting Pyr-/Cbz-based building blocks 1a/b have been
readily prepared from benzylated H-Glu-Z (ee g 99%) using a
modified Clauson-Kaas method12 (2,5-dimethoxytetrahydro-
furan (DMT), NaOAc, AcOH, H2O, 76 °C, 2 h, 50% yield for
1a and DMT, dioxane, reflux, 3 h and room temperature,
overnight, 30% yield for 1b). DCC/HOBt-mediated activation
of acids 1a/b (CH2Cl2 (DCM), 20 °C, 3 h, Scheme 1) was
followed by primary NH2 selective condensation with triamine
2 affording corresponding benzylated bisamides 3a/b in good
yields (81 and 75%, respectively). Traces of triamide benzyl
(Bn) esters 8a/b (Scheme 2, < 5%, TLC) formed were readily
eliminated during purification (flash chromatography on silica
gel, 5% MeOH in DCM). Importantly, amidations did racemize
neither the enantiomerically pure building blocks 1a/b nor
resulting bisamides 3a/b as evidenced by the formation of single
diastereomerically pure C2-symmetrical amidation products (13C
NMR analysis of crude products, absence of meso-diastereo-
mers).
Surprisingly, amidation yields were significantly lower
(∼40%) when the water-soluble carbodiimide N′-(3-dimethyl-
amino-propyl)-N-ethylcarbodiimide hydrochloride (EDC) was
used in place of DCC although both crude workup and
purification of bisamide products were easier. Carbonyl diimi-
dazole-based coupling amidations, that were reported to be
efficient and highly selective with triamine linker 2,13 were also
inefficient under various conditions (reagent concentrations,
solvents, temperatures) leading to monoamide condensation
products in a 70-80% yield range (TLC).
The Bn group deprotection posed a challenge in some of the
above-prepared multifunctional monomers. First trials involved
transfer hydrogenation using 10% Pd/C-cyclohexene at reflux
in i-PrOH for 2 h. Previous studies from the same laboratory
indicated that this system was fully satisfactory in order to
cleanly deprotect simpler C2-symmetrical bis-carbazole bis-Bn
ester monomers (30-60 min, > 95% yield). But these more
complex sterically hindered polyfunctional monomers 4-5a/b
and 8a/b could not undergo complete debenzylation toward
corresponding polycarboxylated monomers 6-7a/b and 9a/b
1
even after overnight reaction at reflux. H NMR spectra (300
MHz, DMSO-d6) and FAB-MS spectrometry analyses per-
formed on partially purified reaction crudes (filtration on a silica
gel column, DCM/MeOH mixtures) showed the presence of
variable amounts of partially debenzylated compounds. The lone
exception being the tetra-Pyr-containing compound 4a (Bn ester)
that, according to the above cleavage conditions, gave the
desired tetra-Pyr tetra-acid 6a in a good 65% yield. Alterna-
tively, hydroxyapatite-bound Pd catalyst, reported as an efficient
debenzylating agent14 for dendrimeric polybenzylated substrates
also completely failed to react. After a large screening work
(various catalysts, solvent, and temperature conditions), poly-
benzylated Pyr-/Cbz-containing intermediate compounds 4-5a/b
and 8a/b were cleanly cleaved under milder room-temperature
The presence of the free internal NH group in benzylated
bisamide building blocks 3a/b allowed a further clean condensa-
tion with both di- and trifunctional acid chlorides of 1,4-di- and
1,3,5-benzene tricarboxylic acids. These amidations provided
key C2-/C3-symmetrical benzyl esters 4a/b and 5a/b, respec-
tively, in good yields (DCM, anhydrous Et3N, 20 °C, 2 h; 4a/
(12) Elming, N.; Clauson-Kaas, N. Acta. Chim. Scand. 1952, 867-874.
(13) Rannard, S. P.; Davis, N. J. Org. Lett. 2002, 2, 2117-2120.
(14) Murata, M; Hara, T; Mori, K; Ooe, M.; Mizugaki, T.; Ebitani, M.;
Kadena, K. Tetrahedron Lett. 2003, 44, 4981-4984.
J. Org. Chem, Vol. 71, No. 24, 2006 9141

Govindaraji et al.
FIGURE 1. (a) Cyclic voltammograms for the electropolymerization of carboxylated hexaCbz-based monomer 7b (5 mm L Pt disk electrode); (b)
voltammetric response of resulting conducting polyCbz-film poly(7b) in supporting electrolyte only (without monomer).
conditions in nonalcoholic THF solvent using H2 gas affording
corresponding white foamy polyCOOH monomers 6-7a/b and
9a/b (10% Pd/C, 20 °C, H2, 12 and 36 h for Pyr- and Cbz-
based monomers, respectively; 6a/6b, 67/71%; 7a/b, 71/69%;
9a/b, 77/74%).
correspond to, respectively, polymer charging (doping) and
monomer oxidation to produce polyCbz polymers. During
electropolymerization, peak currents around 0.6 V increased by
a 20-30% factor for each scan reflecting a polymer growths
increase of the effective polymer surface areaswhile, excluding
the first scan, peaks around 0.85 V almost did not change. In
the typical behavior measurement (Figure 1b, monomer-free
electrolyte), the cyclic voltammogram profile disclosed anodic
peaks which appeared at the same potentials (0.6 and 0.85 V).
The observed peak located around 0.85 V resulted from the
oxidation of free discrete Cbz units that were not part of the
polymeric network (dangling Cbz heterocycles) as demonstrated
previously.15 Accordingly, the ratio i0.85V/i0.6V between higher
and lower potential anodic peaks was closer to unit in this case
rather than in polymerization voltammograms (Figure 1a).
Indeed, in polymerization voltamogramms, peaks around 0.85
V indicated the oxidation of both electrolyte-contained and
polymer-linked Cbz heterocycles. Similar electrochemistry-
related considerations were already explained in detail for the
electro-oxidation (polymerization) of the typical Cbz-based
pentafluorophenyl ester 10b.15 Both polymerizations and char-
acteristic electrochemical behaviors of the other two Cbz-based
monomers 6b/9b and polyCbz-matrices poly(6b)/poly(9b) much
resembled the results disclosed in Figure 1.
Quite interestingly, Pyr-containing acidic monomers 6-7a
and 9a neither polymerized nor oligomerized in these conditions.
The formation of reversible redox peak systems, which char-
acterized the deposition of insoluble conductive poly(N-alkyl
Pyr)-based polymeric networks16 via corresponding cation
radicals, was never observed whatever electrochemical condi-
tions investigated. This unexpected behavior may be tentatively
explained by comparing steric and electrophilicity factors which
characterize Pyr/Cbz-containing cation radicals 11a/b generated
at the initiation polymerization step (Scheme 2). Pyr-containing
cation radicals 11a may be readily trapped intramolecularly by
close nucleophilic acidic hydroxyl groups toward Pyr-based
cycloadducts 12a (five-membered ring-mediated cyclo-alkoxyl-
ation onto the electrophilic nonhindered CR position). Cycload-
ducts 12a may then undergo classical radical dimerization and/
or oxidation (re-aromatization) resulting in polymerization
blocking.17 In contrast, Cbz-containing cation radicals 11b
disclose a more hindered less electrophilic CR position owing
Polycarboxylated acids were unambiguously characterized by
1
a combination of H/13C NMR (300 and 75 MHz, DMSO-d6,
disappearance of signals at δ ∼5.10 and ∼67.0 ppm, respec-
tively, corresponding to CH2-groups of Bn esters) and mass
spectrometry analyses (presence of single molecular ion peaks).
Traces of entrapped solvents were always detected by 1H NMR
although these compounds were dried under high vacuum (10-2
Torr, 2 days). Most likely, this resulted from their foamy nature
as well as from their limited solubility in current organic solvents
except DMSO. Both benzylated and free acidic intermediates/
monomers showed 1H- and 13C NMR (300 and 75 MHz,
CDCl3, and/or DMSO-d6) C/H-related peak broadening and
magnetic asymmetry even for structurally symmetrical two-arm
wedge-substituents arising from 3a/b-related units. This may
be attributed to the presence of equilibrated secondary/tertiary
amide rotamers at the time scale of NMR analysis.
Electro-oxidation features of monomers 6-7a/b, and 9a/b
were investigated by cyclic voltammetry (100 mV/sec) onto a
5 mm diameter Pt disk working electrode using a three-electrode
cell (Pt ribbon counter-electrode, Ag/AgNO3 reference electrode)
operated between zero and 1.2 V (for Cbz-monomers) and -0.5
and 1.2 V (for Pyr-monomers). The background electrolyte
consisted of 0.2 M n-Bu4NClO4 and 0.2 M LiClO4 in a 1/2 v/v
ethylenecarbonate-dimethylcarbonate solution in which mono-
mer concentrations were adjusted to 1.0 mM.
All Cbz-based acidic monomers 6-7b, and 9b were found
to readily electropolymerize onto the Pt disk-working electrode
toward corresponding conducting films. Following the polym-
erization process, the typical electrochemical behavior of so-
produced polyCbz-polymers was also measured in the support-
ing (monomer-free) electrolyte at the same voltage range and
sweep rate.
An illustrative cyclic voltammogram of the electropolymer-
ization process of the densely functionalized polyCOOH Cbz-
based monomer 7b and its typical electrochemical behavior have
been reported in Figure 1. Voltammogram analysis was based
on former conclusions relating to the electropolymerization of
typical 2,6-bis-carbazole-9-yl-hexanoic acid (pentafluorophenyl
ester) monomer 10b (Scheme 2) and characterization of cor-
responding polydicarbazole-type polymer.15 The two reversible
peaks that appeared around 0.6 and 0.85 V in the anodic scan
(15) Diamant, Y.; Furmanovich, E.; Landau, A.; Lellouche, J.-P.; Zaban,
A. Electrochim. Acta 2003, 48, 507-512.
(16) (a) Zhou, M.; Heinze, J. Electrochim. Acta 1999, 44, 1733-1748.
(b) Deronzier, A.; Moutet, J.-C. Curr. Top. Electrochem. 1994, 3, 159-200.
9142 J. Org. Chem., Vol. 71, No. 24, 2006

Carboxylated Pyrrole- and Carbazole-Based Monomers
dibenzylated dipyrrole-amine 3a (2.600 g, 2.05 mmol) in anhydrous
DCM (40 mL) followed by terephthaloyl chloride (0.406 g, 2.0
mmol, dry N2, 20 °C) in one portion. The reaction mixture was
allowed to stir until completion (∼1 h, TLC checking). Then, the
reaction mixture was washed with distilled water (2 × 20 mL) and
brine (1 × 20 mL), dried on dry Na2SO4, and filtered (5 µm Bu¨chner
filter). Following concentration of the filtrate under vacuum, the
resulting crude condensation compound was purified by flash
chromatography on a silica gel column (40-60 mesh) eluted by a
7/3 v/v DCM/MeOH mixture affording the pure compound 4a
(2.010 g, 70% yield) as a pale yellow viscous oil. FT-IR (KBr pellet,
ν in cm-1): 700 (m), 731 (s), 804 (s), 864 (w), 1024 (s), 1094 (s),
1175 (s), 1262 (s), 1379 (w), 1427 (m), 1545 (s), 1651 (s), 1741
to the presence of additional phenyl rings (higher degree of CR
substitution and increased charge delocalization, respectively)
in Cbz-units. Therefore, generation of corresponding Cbz-based
cycloadducts 12b is highly disfavored allowing polymer chain
propagation from reactive peripherally localized cation radicals
of type 11b. This explanation is strongly supported by similar
observations recently made during the unsuccessful electro-
oxidation of a range of N-(hydroxyalkyl) Pyr-based monomers
owing to intramolecular HO-mediated cycloalkoxylations.18
In conclusion, we have simply designed and readily synthe-
sized six novel functional polycarboxylated Pyr-/Cbz-based
monomers that contained three, four, and six electro-oxidizable
outer decorating Pyr-/Cbz-units and COOH groups. Additionally
and for the first time, the three reported polycarboxylated Cbz-
containing monomers 6-7b and 9b were successfully elec-
tropolymerized on a Pt electrode affording corresponding
electroconductive polycarboxylated polyCbz-films poly(6-7b)
and poly(9b), respectively. Our current efforts are now directed
at the development of suitable applications of these functional
(polyCOOH) electroactive chiral films2c for analyte sensing
through the covalent attachment of a range of biological probes
(DNA sequences, proteins/antibodies, oligosaccharides) onto
them (COOH-related covalent grafting).
1
(s), 2885 (w), 2967 (m), 3068 (w), 3299 (s). H NMR (300 MHz,
CDCl3): δ 1.87-2.30 (m, 16H), 3.10-3.19 (m, 8H), 3.42-3.59
(m, 8H), 3.56-3.65 (m, 4H), 4.62 (m, 2H), 4.73 (m, 2H), 5.11 (s,
8H), 6.14 (s, 8H), 6.50 (bs, 2H), 6.65-6.69 (s, 8H), 7.11 (bs, 2H),
7.12-7.33 (m, 26 H). 13C NMR (75 MHz, CDCl3): δ 28.3, 31.7,
37.9, 39.0, 45.9, 49.4, 60.9, 67.3, 109.0, 109.3, 120.3, 126.6, 128.1,
128.5, 128.7, 135.3, 137.1, 170.1, 170.3, 172.1, 172.5. FAB-MS
(glycerol matrix, positive mode ionization): m/z 1414 [MD+,
100%], 1145 (49%), 1132 (41%), 1038 (17%), 976 (12%). FAB-
HRMS (glycerol matrix, positive mode ionization): m/z calcd for
C80H88N10O14 [M], 1412.6481; found, 1412.6472 (3.0 mDa). [R]25
-16.4 (c 3.8, THF).
D
A Typical Debenzylation Procedure of Pyr-/Cbz-Containing
Dendrimers. 4-(2-{(4-{Bis-[2-((S)-4-carbazol-9-yl-4-carboxy-bu-
tyrylamino)-ethyl]-carbamoyl}-benzoyl)-[2-((S)-4-carbazol-9-yl-
4-carboxy-butyrylamino)-ethyl]-amino}-ethylcarbamoyl)-(S)-2-
carbazol-9-yl-butyric Acid (6b). A suspension of 10% Pd/C (0.20
g), in THF (10 mL) containing tetracarbazole benzylester 4b (1.00
g, 0.55 mmol) was stirred under a H2 atmosphere for 48 h at room
temperature. Removal of the Pd/C catalyst was effected by filtration
through a celite bed (250 mg). Then, the filtrate was concentrated
under vacuum, and the resulting crude product purified by flash
chromatography on a silica gel column (40-60 mesh) eluted by a
DCM/THF mixture (gradient from 80% v/v DCM/THF to 10% v/v
DCM/THF). It afforded the chromatographically pure compound
6b (0.57 g, 71%) as a pale yellow foamy solid (mp: 218-220
°C). FT-IR (neat, ν in cm-1): 724 (m), 754 (s), 1079 (w), 1240
(s), 1333 (s), 1452 (s), 1483 (m), 1551 (m), 1628 (s), 1728 (s),
2943 (s), 3057 (s), 3398 (s). 1H NMR (300 MHz, CDCl3): δ 1.39
(bs, 2H), 1.75 (m, 4H), 2.06 (bs, 2H), 2.34 (bs, 2H), 2.50 (bs, 4H),
2.66 (2H), 2.80 (bs, 4H), 2.90 (bs, 4H), 3.22 (bs, 4H), 3.32 (bs,
4H), 5.54 (bs, 2H), 5.69 (bs, 2H), 6.94 (bs, 4H), 7.21 (bs, 8H),
7.43-7.52 (m, 18H), 7.85 (bs, 2H), 8.16-8.33 (bs, 6H). 13C NMR
(75 MHz, CDCl3): δ 25.2, 31.5, 36.4, 36.7, 44.3, 48.1, 55.7, 109.9,
119.1, 120.3, 122.6, 125.8, 126.1, 137.0, 139.9, 170.2, 171.2, 171.5,
171.7, 171.8. TOF-MS (ES+): m/z 1454 [MH+, 23%], 663 (40%),
529 (23%), 342 (100%), 286 (75%). FAB-HRMS (negative mode
ionization, m-nitrobenzyl alcohol matrix): m/z calcd for C84H79N10O14
Experimental Section
A Typical DCC/HOBt-Mediated Amidation Protocol (Illus-
trated for Intermediate Compound 3a). 4-{2-[2-((S)-4-Benzyloxy-
carbonyl-4-pyrrol-1-yl-butyrylamino)-ethylamino]-ethylcarbam-
oyl}-(S)-2-pyrrol-1-yl-butyric Acid Benzyl Ester (3a). HOBt,
(0.690 g, 5.1 mmol) was suspended in anhydrous DCM (10 mL)
and added to a solution of (i) DCC (1.029 g, 5.3 mmol) and (ii)
monobenzylated Pyr-acid 1a (1.429 g, 4.98 mmol) in DCM (20
mL). The reaction mixture was stirred for 1 h at 20 °C. The precip-
itated dicyclohexylurea (DCU) was discarded by filtration (5 µm
Bu¨chner filter). Then, the triaminated linker 2 (0.256 g, 2.4 mmol)
was dissolved in anhydrous DCM (5 mL) and then added dropwise
to the resulting clear filtrate solution. The reaction mixture was
gently agitated for a further 15 min and evaporated under vacuum.
Purification of the crude compound has been performed on a silica
gel column (40-60 mesh, eluent: 6/4 v/v DCM/MeOH mixture)
in order to afford the chromatographically pure dibenzylated
dipyrrole-amine 3a (1.290 g, 81% yield) as a pale yellow mobile
oil. FT-IR (neat, ν in cm-1): 736 (s), 1094 (m), 1177 (s), 1269 (s),
1387 (w), 1448 (w), 1492 (w), 1547 (s), 1657 (s), 1739 (s), 2831
1
(w), 2890 (m), 2943-44 (m), 3065 (s), 3403 (m). H NMR (300
MHz, CDCl3): δ 1.82-1.84 (m, 2H), 2.20 (m, 2H), 3.00 (m, 2H),
3.39 (m, 2H), 4.50 (m, 1H), 5.03 (s, 2H), 6.03 (s, 2H), 6.54 (s,
2H), 7.16-7.26 (m, 3H), 7.26 (m, 3H), 7.46 (m, 1H), 7.56 (m,
1H), 7.91 (m, 2H), 8.94 (bs, 2H). 13C NMR (75 MHz, CDCl3) δ
27.8, 31.3, 36.5, 47.9, 60.8, 67.1, 108.7, 110.9, 118.2, 120.0, 124.7,
127.4, 127.9, 128.3, 128.45, 128.6, 135.1, 142.9, 170.1, 172.8. TOF-
MS (ES, positive mode ionization): m/z 642 [MH+, 100%], 534
(28%), 467 (12%), 136 (17%). FAB-HRMS (positive mode,
m-nitrobenzyl alcohol matrix): m/z calcd for C36H43N5O6 [M],
641.3254; found, 641.3251 (5.0 mDa). [R]25D -4.1 (c 5.56, DCM).
A Typical Acylation Procedure Using Acid Chlorides. 4-{2-
[[2-((S)-4-Benzyloxycarbonyl-4-pyrrol-1-yl-butyrylamino)-ethyl]-
(4-{bis-[2-((S)-4-benzyloxycarbonyl-4-pyrrol-1-yl-butyrylamino)-
ethyl]-carbamoyl}-benzoyl)-amino]-ethylcarbamoyl}-(S)-2-pyrrol-
1-yl-butyric Acid Benzyl Ester (4a). Anhydrous triethylamine
(1.010 g, 10.0 mmol) was added to a solution of intermediate
[M - H], 1451.5777; found, 1451.5782 (-0.6 mDa). [R]25 -52.3
D
(c 2.1, THF).
Acknowledgment. This work has been partly funded under
both Vth and VIth Framework European CHEMAG (Grant
GRD2-2000-30122) and NACBO (Grant NMP3-2004-500802-
2) projects.
Supporting Information Available: Characterization data of
compounds 1a/b, 3-4b, 5-6a, 5b, 7a/b, 8a/b, and 9a/b; cyclic
voltammograms for the electropolymerization of polycarboxylated
tri/tetraCbz-based monomers 9b and 6b (5 mm L Pt disk electrode)
that included corresponding voltammetric responses of resulting
conducting polyCbz-films Poly(9b) and Poly(6b) in supporting
electrolyte (without monomer). This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) (a) Schuhmann, W. Mikrochim. Acta 1995, 121, 1-29. (b) Pham,
M. C.; Hachemi, A.; Dubois, J. E. J. Electroanal. Chem. Interfacial
Electrochem. 1984, 161, 199-204.
(18) Bidan, G,; Guglielmi, M. Synth. Met. 1986, 15, 49-58.
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