A simple and environmentally benign synthesis of polypyridine- polycarboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2010.12.074

An oxidation method using dilute nitric acid solutions under solvothermal conditions has been developed to synthesise a series of polypyridine- polycarboxylic acids. It has been successfully applied to a range of methyl substituted polypyridines including symmetrical and asymmetrical 2,2′-bipyridines; 2,2′:6′,2″-terpyridines and; 2,2′:6′,2″:6″,2?-tetra-pyridines and yields crystalline polypyridine-polycarboxylic acids in a single step. Simple product recovery through filtration yields a recyclable filtrate. More forcing conditions led to demethylation of the polypyridine ligand most probably via decarboxylation. This simple approach avoids potentially harmful metal-based oxidants and negates any issues associated with the disposal of their resultant (hazardous) waste.

Full text of DOI:10.1016/j.tetlet.2010.12.074

Tetrahedron Letters 52 (2011) 995–998
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple and environmentally benign synthesis of
polypyridine-polycarboxylic acids
Niamh R. Kelly a, Sandrine Goetz a, Chris S. Hawes b, Paul E. Kruger b,
⇑
a School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
b Department of Chemistry, University of Canterbury, Christchurch 8020, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
An oxidation method using dilute nitric acid solutions under solvothermal conditions has been developed
to synthesise a series of polypyridine-polycarboxylic acids. It has been successfully applied to a range of
methyl substituted polypyridines including symmetrical and asymmetrical 2,20-bipyridines; 2,20:60,200-
terpyridines and; 2,20:60,200:600,2000-tetra-pyridines and yields crystalline polypyridine-polycarboxylic acids
in a single step. Simple product recovery through filtration yields a recyclable filtrate. More forcing con-
ditions led to demethylation of the polypyridine ligand most probably via decarboxylation. This simple
approach avoids potentially harmful metal-based oxidants and negates any issues associated with the
disposal of their resultant (hazardous) waste.
Received 22 October 2010
Revised 7 December 2010
Accepted 17 December 2010
Available online 23 December 2010
Keywords:
Environmentally benign
Polypyridine-polycarboxylate
Oxidation
Ó 2010 Elsevier Ltd. All rights reserved.
Solvothermal
2,20-Bipyridines
The polypyridine family of molecules attract significant atten-
tion as important chelating ligands due to their ability to form ex-
tremely stable complexes with metal ions from across the periodic
table.1 The continued interest is driven by the myriad properties
possessed by these complexes ranging from photo-chemical and
analytical-based materials, through catalytic and electro-catalytic,
to anti-proliferative and biological activity.2 Indeed, considerable
current interest surrounds their use in metallo-supramolecular
chemistry incorporating the formation of both discrete species
(e.g., helicates, catenates, etc.)3 and coordination polymers with
the porous analogues of the latter (metal-organic frameworks)
possessing potential applications in gas storage and sequestration,
catalysis, magnetic materials, host-guest behaviour, etc.4 More-
over, the 2,20-bipyridine-poly-carboxylate based ligands have been
used extensively to anchor metal complexes to surfaces and have
found utility in dye-sensitised solar cell applications such as within
the Grätzel cell.5
The realisation of these goals in an expedient manner requires
effective, reliable and, where possible, sustainable synthesis of
the poly-pyridine molecules. This has been realised by either tradi-
tional Kröhnke type pyridine synthesis, or more efficiently by me-
tal-mediated coupling of suitable pyridine precursors.6
Derivatisation of the poly-pyridine scaffold most often involves
functionalisation of methyl (alkyl) substituents via oxidation to
their corresponding alcohols or carboxylic acids. To date the
synthesis of carboxylate-containing polypyridines (and related li-
gands) has been dominated by the use of metal-based oxidants,
such as K2Cr2O7 and KMnO4, in corrosive media, to generate the
carboxylic acid from an appropriate alkyl or similarly substituted
precursor. Whilst this approach typically has wide application, it
is encumbered by serious potential health risks and associated
waste disposal issues. Indeed, a one gram scale synthesis of 4,40-
dicarboxyl-2,20-bipyridine involves the slow addition of ca. 8.0 g
of K2Cr2O7 to 4,40-dimethyl-2,20-bipyridine in ca. 50 ml of concen-
trated H2SO4, and the isolated solid is subsequently refluxed in ni-
tric acid (50 ml) to ensure complete oxidation.7 This generates
litres of aqueous waste solution after work-up for disposal. More-
over, the use of KMnO4 often requires careful portion-wise addi-
tion of the oxidant to aqueous solutions of the substrate over
several hours whilst maintaining careful, and sometimes variable,
temperature control. Furthermore, product recovery is often com-
plicated by the intractable nature of the MnO2 by-product and
time-consuming filtration. Additionally, the success of either
method may be variable across a family of related ligands and of-
ten delivers inconsistent yields.
Our attraction to the polypyridine-poly-carboxylate ligands is
driven by the fact that, in principle, each functional group may
coordinate to every metal within the periodic table, either singly
or in unison, to generate innumerable complexes. Our research ef-
fort has incorporated the use of several of these ligand types in the
synthesis of coordination polymers in conjunction with metal ions
from across the main group, transition and lanthanide series.8 To
realise these ends effectively, we required expedient and reliable
syntheses of poly-carboxylic acid based ligands and wished to
⇑
Corresponding author. Tel.: +64 3 364 2438; fax: +64 3 364 2110.
E-mail address: paul.kruger@canterbury.ac.nz (P.E. Kruger).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.074

996
N. R. Kelly et al. / Tetrahedron Letters 52 (2011) 995–998
move away from the metal-based oxidants because of the short-
HO
OH
O
O
comings mentioned above. We have, therefore, developed a simple
method which employs dilute aqueous nitric acid solutions (4%)
and follows a simple solvothermal protocol that gives crystalline
products in a single step in better yields than those achieved
through traditional methods. Simple product recovery through fil-
tration yields a recyclable filtrate, Scheme 1. It should be noted
that simply refluxing these molecules in concentrated nitric acid
does not affect any viable oxidation and, therefore, the solvother-
mal approach is necessary.
Me
Me
4% aq. HNO3
N
N
N
N
solvothermal
n
n
T = 160 °C; 36 h
n = 1, 2 or 3
n = 1, 2 or 3
Scheme 1. Polypyridine substrates used to generate the corresponding polypyri-
dine-polycarboxylic acids via aqueous nitric acid oxidation under solvothermal
conditions.
Table 1
Polypyridine substrates used to generate the corresponding polypyridine-polycarboxylic acids via Scheme 1

N. R. Kelly et al. / Tetrahedron Letters 52 (2011) 995–998
997
Table 1 (continued)
a1H NMR: 400 MHz, DMSO-d6; IR as KBr pellet; L1a, L2a, L4a, L7a, L8a and L11a were also structurally characterised (to be reported elsewhere).
The ease of this approach is best illustrated by considering the
synthesis 4,40-dicarboxyl-2,20-bipyridine (L1a), which results from
the oxidation of 4,40-dimethyl-2,20-bipyridine (L1) and comparing
this to the K2Cr2O7 method mentioned above, Table 1. L1 (200 mg;
1.08 mmol) was suspended in water (8 mL) and concentrated
HNO3 (0.5 mL) was added dropwise with stirring and the mixture
placed into a 23 ml TeflonÒ-lined stainless steel bomb.9 The bomb
was heated at 160 °C for 36 h and then slowly cooled to rt (10 °C/
h) to give large colourless needles of L1a, which were filtered,
washed with water (2 ꢀ 10 mL) and air dried. L1a was isolated in
a 70% yield and its identity confirmed by satisfactory spectroscopic
and microanalytical data and single crystal X-ray diffraction Table 1.
This single-step method is far superior to the dichromate procedure,
as it does not require any subsequent work-up which negates haz-
ardous waste disposal issues and gives a crystalline product directly
in comparable yield. Indeed, simply replenishing the acidic filtrate
with a new batch of L1 and repeating the heating cycle again yields
L1a, although in a slightly diminished yield (ca. 55%). This cycle can
be repeated twice more with no further diminution in yield. Increas-
ing the initial loading of L1 threefold came at the expense of yield
(40%) and purity, with trace L1 remaining. Using longer heating
times did not increase the yield of L1a and higher temperatures
caused decarboxylation (vide infra).
Encouraged by these results we then surveyed the scope of the
method towards the oxidation of various other polypyridine li-
gands. We first investigated the symmetrical and asymmetrical di-
methyl-2,20-bipyridine isomers L2–L6, and again found that
crystalline products L2a–L6a were obtained in up to 70% isolated
yields following this single-step procedure Table 1. L2a and L3a
are well known molecules although now obtained directly,10
whereas L4a and L5a appear only once in the literature, and were
then only obtained with difficultly in moderate 60% and poor 13%
yields, respectively.11 L6a is a novel ligand and was obtained here-
in for the first time in 55% yield. Our prior efforts at synthesising
L6a via either of the traditional metal-based oxidation methods
never succeeded. Indeed, when trying to oxidise any dimethyl-
2,20-bipyridine scaffold featuring substitution at the 5 (or 50) posi-
tion, we always suffered poor reproducibility, product purity and
yield.
analogue L7a via dichromate-mediated oxidation.12 Application
of the current procedure to the preparation of L7a resulted in a dis-
appointingly low 20% isolated yield, along with non-oxidised L7
(ca. 50%) and other non-identifiable products. In an effort to in-
crease the yield of L7a we employed more forcing conditions by
elevating the temperature to 200 °C. This led to the isolation of col-
ourless needles in 45% yield, which had both spectroscopic and X-
ray crystallographic properties consistent with the formation of
4,40-dicarboxyl-2,20-bipyridine, L1a. Evidently, more forcing condi-
tions led to the double decarboxylation. Lowering the temperature
to a ‘milder’ 180 °C gave a colourless solution from which colour-
less crystalline plates were isolated in 41% yield after standing
for one week. Elemental analysis and spectroscopic data were con-
sistent with the formation of a novel mono-decarboxylated prod-
uct, L8a, which was also confirmed through single crystal X-ray
diffraction. This method is, therefore, a viable route to the synthe-
sis of this unsymmetrical product, which would be difficult to ob-
tain through more conventional synthetic means. Furthermore,
using a range of temperatures in an attempt to oxidise L8 and L9
did not return any tetra-carboxylic species only giving the di-car-
boxylic species, L1a and L2a, respectively, which again presumably
result from double decarboxylation of the tetra-methyl precursors
following (partial) oxidation. Indeed, we were similarly unable to
oxidise satisfactorily either L8 or L9 to their corresponding tetra-
carboxylic acids through any of the traditional metal oxidant based
routes. In fact, to date neither of these putative tetra-carboxylic
acids has been reported in the literature.
We also screened this method against the oxidation of more re-
mote methyl substitution by looking at L10–L12, which feature p-
tolyl-substituted bi-, tri- and tetra-pyridine scaffolds. Gratifyingly,
this led to the formation of the corresponding carboxylic acids
L10a–L12a in 75%, 70% and 65% yields, respectively. It should be
noted that neither L10a nor L12a has been reported in the litera-
ture to date.
As an extension to this current work we also briefly examined
the application of this method towards the oxidation of 3,5-
dimethylpyrazole (3,5-dmpz)-based molecules. The oxidation of
3,5-dmpz to its corresponding dicarboxylic acid was unsuccessful
producing only poorly identifiable degradation products. Satisfy-
ingly though, the oxidation of 4-(4-pyridyl)-3,5-dimethylpyrazole
(Py-3,5-dmpz) yielded 4-(4-pyridyl)-pyrazole (Py-pz), presumably
via in situ decarboxylation, Scheme 2.
We next moved to investigate this approach towards the oxida-
tion of the tetra-methyl-2,20-bipyridine isomers L7–L9. We previ-
ously reported the synthesis of L7 and its tetra-carboxylic

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N. R. Kelly et al. / Tetrahedron Letters 52 (2011) 995–998
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Py-pz
Scheme 2. Solvothermal heating of Py-3,5-dmpz in aqueous nitric acid produced
Py-pz following in situ decarboxylation.
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Acknowledgements
The authors thank the University of Canterbury (College of
Science Scholarship to C.S.H.), the Royal Society of New Zealand
Marsden Fund, Science Foundation Ireland and HEA-PRTLI Cycle
3 and Cycle 4 (CSCB) for financial support. The authors thank
Professor Peter Steel and Dr. Anthea Lees (UC) for helpful
discussions.
References and notes
1. Smith, A. P.; Fraser, C. L. Bipyridine Ligands In Comprehensive Coordination
Chemistry II; McCleverty, J. A., Meyer, T. J., Eds.; Elsevier, 2003; Vol. 1, pp 1–23;