Syntheses and studies of flexible amide ligands: a toolkit for studying metallo-supramolecular assemblies for anion binding

Article abstract of DOI:10.1016/j.tet.2009.04.031

The syntheses of seven flexible bidentate bis-pyridyl diamide and four monodentate pyridyl amide ligands containing central amide units are described. The bis-pyridyl ligands were prepared in one step from commercially available compounds in moderate to g

Full text of DOI:10.1016/j.tet.2009.04.031

Tetrahedron 65 (2009) 4681–4691
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses and studies of flexible amide ligands: a toolkit for studying
metallo-supramolecular assemblies for anion binding
,
b
Christopher J. Sumby a , Lyall R. Hanton
*
a School of Chemistry & Physics, University of Adelaide, Adelaide, SA Australia
b Department of Chemistry, University of Otago, Dunedin, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of seven flexible bidentate bis-pyridyl diamide and four monodentate pyridyl amide ligands
containing central amide units are described. The bis-pyridyl ligands were prepared in one step from
commercially available compounds in moderate to good yield. These compounds all possess external metal
coordinating pyridyl groups and internal amide functionalities, with the potential to bind anions. Crystal
structures of six of the bis-pyridyl diamide ligands are described. The four compounds with xylene cores
N,N0-[1,3-phenylenebis(methylene)]bis-3-pyridinecarboxamide 1, N,N0-[1,3-phenylenebis(methylene)]bis-
Received 22 October 2008
Received in revised form 11 March 2009
Accepted 9 April 2009
Available online 17 April 2009
4-pyridinecarboxamide 2, N,N0-[1,4-phenylenebis(methylene)]bis-3-pyridinecarboxamide
3
and N,N0-
[1,4-phenylenebis(methylene)]bis-4-pyridinecarboxamide 4 crystallize with extensive amide N–H/O]C
hydrogen bonding between the diamide compounds, giving rise to two and three dimensional hydrogen
bonded networks. N,N0-Bis(3-pyridylmethyl)benzene-1,3-dicarboxamide 5, the only compound with the
amide groups directly attached to a central benzene core, was not able to be crystallised. N,N0-2,6-Bis(3-
pyridylmethyl)pyridine dicarboxamide 6 and N,N0-2,6-bis(4-pyridylmethyl)pyridine dicarboxamide 7 have
a mismatch of hydrogen bond donor and acceptor regions preventing ready involvement of the amide NH
groups in network formation. For comparison we also prepared compounds N,N0-20-propyl-6-(3-pyr-
idylmethyl)pyridine dicarboxamide 10 and N,N0-20-propyl-6-(4-pyridylmethyl)pyridine dicarboxamide 11
with two amide groups but only the one external donor pyridyl moiety, and compounds N-6-[(3-pyr-
idylmethylamino)carbonyl]-2-pyridinecarboxylic acid methyl ester 8 and N-6-[(4-pyridylmethylamino)-
carbonyl]-2-pyridinecarboxylic acid methyl ester 9, which have only the one amide.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
chemistry. The anion binding and encapsulating assemblies of in-
terest can be readily explored using a number of relatively simple
The field of anion binding has rapidly progressed over the last
decade.1–4 This birth of anion coordination chemistry5 originated in
the appreciation of the significant impact anions have in environ-
mental, biological and medicinal arenas. This includes fertilizer
run-off, toxic metallo-anion species and sulfate anion contamina-
tion of low-level nuclear wastes, for example. Strategies to selec-
tively complex anions have been described for a large range of
anions. These include using organic hosts with diverse hydrogen
ligands capable of interacting with anions; the structural com-
plexity required to bind an anion is generated by the choice of
metal ion used to assemble the metallo-supramolecular species
(Fig. 1). Furthermore, labile transition metal centres allow these to
be dynamic assemblies that respond to external stimuli, while the
correct choice of metal centre can add additional scope in terms of
optical or electrochemical responses to binding.
The use of ligands containing hydrogen bond donor groups to
bind anions as part of a transition metal complex or metallo-
supramolecular assembly is not a new strategy. Transition metal
complexes with pendant hydrogen bond donor groups have been
reported by several groups.12–14 Similarly, metallo-supramole-
cular assemblies with internal hydrogen bonding domains have
also been reported.10,15–17 In an effort to generate simple metallo-
supramolecular assemblies to bind anions we focused our
attention on a series of simple relatively flexible mono- and
bis-amido containing heterocyclic ligands. These flexible and
bonding donor groups2,3 and/or -acidic heteroarene scaffolds;6–8
p
electrostatic interactions with cations;1,9 and more recently, met-
allo-supramolecular assemblies10 and coordination polymers.11
The use of a metallo-supramolecular species to bind anions in-
troduces the attendant advantages of metallo-supramolecular
* Corresponding author. Tel.: þ61 8 8303 7406; fax: þ61 8 8303 4358.
E-mail address: christopher.sumby@adelaide.edu.au (C.J. Sumby).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.031

4682
C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
X
X
2+
Y
Y
Y
H
N
H
N
O
O
A-
HN
HN
NH
NH
O
O
O
O
N
N
X = N, Y = CH
X = CH, Y = N
1
2
H2N
NH2
N
Pd
N
O
O
X
Y
N
H
H
N
X
M
A-
M
X = N, Y = CH
X = CH, Y = N
3
4
A-
O
O
M
N
H
N
H
(b)
(a)
N
X
N
X
Figure 1. Schematic representations of the targeted metallo-supramolecular assem-
5
blies formed with (a) monodentate and (b) bidentate ligands.
O
O
N
N
N
H
accommodating assemblies should be capable of binding a range
of anionic guests.
H
Y
Y
The ligands we have based our studies on are shown in Diagram
1. These include the ligands of primary interest (1–7), which pos-
sess two external pyridyl metal coordinating sites and two internal
amido groups, compounds 8 and 9 with two amido groups but only
the one external donor pyridyl moiety, and 10 and 11, which have
only the one amide. Herein we describe the syntheses of these
compounds and the crystal structures of six of the bis-amido
bridging ligands.
X = N, Y = CH
X = CH, Y = N
6
7
O
O
N
O
N
H
Y
X
X
X = N, Y = CH
X = CH, Y = N
8
9
2. Results and discussion
2.1. Syntheses
O
O
N
N
N
H
H
Y
In our strategy to use simple organic ligands to bind anions
within metallo-supramolecular assemblies we required a relatively
simple and direct route to our desired compounds. The choice of
amide hydrogen bond donor groups was made for two primary
reasons; amide hydrogen bond donors are commonly used to bind
anions and they can be readily prepared on a large scale in high
yielding reactions. One issue we wished to avoid was the low sol-
ubility of many amide derivatives; this prompted us to opt for ad-
ditional flexibility through the use of xylyl, instead of benzene,
spacers in 1–4 and the picolyl group in compound 5. Furthermore,
the additional length of the diamides would allow for the formation
of slightly larger metallo-supramolecular structures capable of ac-
commodating larger guest species within the resulting cavities.
Oddly, very little attention has been paid to these particular flexible
bis-amides. Compound 1 has been studied with regard to blood
platelet aggregation,18 while compounds 2–4 have not been
reported before and the only description of compound 5 is as an
anti-oxidant in lubricating grease.19 The 4-pyridyl isomer of com-
pound 5, N,N0-bis(4-pyridylmethyl)benzene-1,3-dicarboxamide, A
(Diagram 2) has attracted considerably more attention,17, 20 while
N,N0-bis(3-pyridylmethyl)benzene-1,4-dicarboxamide, B and N,N0-
bis(4-pyridylmethyl)benzene-1,4-dicarboxamide, C have also been
previously prepared and crystal structures of the bis-amides and
their complexes reported.21–23 Related compounds lacking the
methylene spacer, and concomitant additional flexibility, have also
been studied.24 Flexible diamides with aliphatic cores have also
attracted attention.25
X = N, Y = CH 10
X = CH, Y = N 11
Diagram 1.
diamine. These were isolated in good yields (54–90%) by a simple
work-up procedure, and characterized by NMR and IR spectros-
copy, mass spectrometry and combustion analysis. In all cases,
crystals of the resulting diamides were obtained that were suitable
for structure determinations by X-ray crystallography. The fifth
isomeric compound 5 was obtained by similar chemistry but with
a reversal of the functional groups of the two reaction partners.
O
O
N
H
N
H
N
Y
N
Y
A
O
X
N
H
H
N
X
O
X = N, Y = CH
X = CH, Y = N
B
C
Compounds 1–4 were prepared by reacting commercially
available nicotinoyl or iso-nicotinoyl chlorides with the correct
Diagram 2.

C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
4683
give compounds 10 and 11 in 68 and 58% isolated yields,
respectively.
2.2. Structure determinations
2.2.1. Structures of N,N0-[1,3-phenylenebis(methylene)]-bis-3-
pyridinecarboxamide chloroform solvate, 1$CDCl3 and N,N0-[1,3-
phenylenebis(methylene)]-bis-3-pyridinecarboxamide 2
In the solid-state structures of diamides 1 and 2 the compounds
adopt an almost identical solid-state conformation and the hy-
drogen bonded networks have an identical topology. Crystals of
1$CDCl3 were obtained by allowing a deuterated chloroform solu-
tion of the compound to slowly evaporate. Compound 1 crystallises
in the monoclinic space P21/c with four complete molecules of 1
and four deuterated chloroform solvate molecules in the unit cell.
Compound 1 adopts a ‘U’-shaped conformation in the solid state
(Fig. 2), with the 3-pyridinecarboxamide groups almost mutually in
plane and perpendicular to the central xylene group. One of the 3-
pyridinecarboxamide moieties is inclined by ca. 14.5ꢀ from per-
pendicular while the other is significantly more twisted at ca. 35.4ꢀ
from perpendicular, reducing the gap between the two arms of the
compound but not sufficient to generate significant intramolecular
Figure 2. A perspective view of the ‘U’-shaped conformation of compound 1. Ellipsoids
shown at 50% probability level and the deuterio-chloroform solvate not shown.
Thus, phthaloyl chloride reacted with 3-pyridylmethylamine to
give compound 5 in 65% isolated yield. The 4-pyridyl derivative of
5, compound A has been prepared by other workers.17,20
The five ligands described above possess relatively flexible
structures with little conformational control over the directionality
of the amide NH hydrogen bond donors. The 2,6-pyridinediamide
moiety has been employed by numerous groups to pre-organize
the two amide NH donors.26 We chose to incorporate this moiety
into our compounds as pre-organized analogues of 1 and 2. Other
groups27 have accessed the 2,6-pyridinediamide moiety from 2,6-
dimethylpyridine dicarboxylate rather than the equivalent acid
chloride. We opted for this route in the synthesis of compounds 6
and 7, by analogy to the successful synthesis of the 2-pyridyl ana-
logue.28 Simply refluxing a suspension of 2,6-dimethylpyridine
dicarboxylate with a greater than twofold excess of 3- or 4-ami-
nomethylpyridine in toluene gave compounds 6 and 7 in 76% and
40%, respectively. These compounds were characterized by NMR
and IR spectroscopy, mass spectrometry and combustion analysis,
and both compounds yielded crystals suitable for structure de-
termination by X-ray crystallography.
Having prepared a series of bidentate ligands with internally
directed hydrogen bond donor groups, we set about preparing the
related mono amide and model diamide derivatives. Compounds
8 and 9 were synthesized using conditions similar to those used
to prepare the potentially bidentate compounds 6 and 7. By al-
tering the stoichiometry of the reaction 8 and 9 were obtained
after column chromatography in 59 and 68% yield, respectively.
These could then be reacted with an excess of propylamine to
p-stacking interactions.
While the compound adopts the generally desired ‘U’-shape the
amide hydrogen bond donors are orientated perpendicular to the
xylene groups and not into the potential ‘cavity’ of the compound.
Within the extended structure the compound 1 forms four N–H/
O]C hydrogen bonds to three other molecules of 1, with distances
fairly typical of moderately strong hydrogen bonds.29 Two of these
hydrogen bonds are to a symmetry-related molecule of 1 leading to
an N–H/O]C hydrogen bonded dimer with d¼1.979 Å and
D¼2.769 Å. The other two N–H/O]C hydrogen bonds are to two
other molecules of 1 with d¼1.995 Å and D¼2.768 Å. Thus, the
overall packing of compound 1 consists of hydrogen bonded dimers
that are hydrogen bonded to four other dimers to give 2-D hydro-
gen bonded sheets that extend within the bc plane of the unit cell
(Fig. 3). Within each hydrogen bonded dimer of 1 the molecules are
lying in opposite directions, allowing for additional weak C–H/
p
interactions between the pyridyl group of one molecule and the
xylene moiety of a second.
If the (1)2 dimers are considered as four-connecting nodes (i.e.,
the internal hydrogen bonds within the dimers are treated as topo-
logically trivial) then the extended structure has a (4,4) network
topology. The two dimensional hydrogen bonded sheets are packed
into layers with the deuterated chloroform molecules sandwiched
between the 4-connected 2-D sheets to complete the 3-D packing of
1$CDCl3.
Figure 4. A perspective view of the ‘U’-shaped conformation of 2, which adopts
a conformation very similar to compound 1 in the solid state. Ellipsoids shown at 50%
probability level.
Figure 3. A perspective view of the extended hydrogen bonded sheet in the bc plane of
1$CDCl3 showing the hydrogen bonded dimers.

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C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
group C2/c with half the ligand molecule, which lies on the twofold
axis, in the asymmetric unit. The compound adopts a zigzag con-
formation with both 3-pyridinecarboxamide arms twisted about
the sp3-CH2 linker at ca. 112.7ꢀ to the xylene core; one arm is di-
rected above and the other below the plane of the central xylene
ring, Figure 5. Bond lengths and angles are unremarkable for such
a compound. The pyridyl donors are oriented in opposing di-
rections as defined by a centre of symmetry passing through the
centroid of the xylene ring.
Each molecule of 3 participates in four hydrogen bonds to four
symmetry-related molecules of 3 and thus, each ligand can be
considered a 4-connecting node. This leads to a (4,4) hydrogen
bonded network, Figure 6, with a zigzag structure when viewed
perpendicular to the plane of the sheet. As the atoms involved in
hydrogen bonding are not at the ends of the molecule, this results
in protrusions of the 3-pyridine rings above and below the sheets.
Association of the layers completes the 3-D packing of the crystal.
Crystals of an isomer of 3 N,N0-bis(3-pyridylmethyl)benzene-1,4-
dicarboxamide dihydrate were reported by Ge et al.22 In that struc-
ture the diamide B adopts a similarconformation tothe one reported
for 3 here; both compounds adopt the anti configuration. In the
structure of compound B the two water solvate molecules mediate
hydrogen bonding interaction between the molecules of the di-
amide. The same diamide was also used to prepare two isostructural
coordination polymers with copper(II) and zinc(II) dinitrate.21 In
those structures compound B adopted a different conformation,
highlighting the generally flexible nature of the ligands.
Figure 5. Two perspective views from the crystal structure of 3 showing the zigzag
conformation of the compound in the solid state. Ellipsoids shown at 50% probability
level. Symmetry operation used to generate complete molecules: ꢁx, ꢁy, ꢁz.
Crystals of 2 were obtained from a methanol solution of 2 and
copper(II) nitrate by slow evaporation. Compound 2 crystallised in
the monoclinic space P21/n with four complete molecules of 2 in
the unit cell. Compound 2 adopts the same ‘U’-shaped conforma-
tion (Fig. 4) as the isomeric ligand 1, with the 4-pyridinecarbox-
amide groups almost mutually in plane and perpendicular to the
central xylene group (twists of ca. 13.2ꢀ and 23.5ꢀ from perpen-
dicular). Again, the hydrogen bond amide donors are not directed
into the ‘U’-shaped cavity of the ligand.
Compound 2 is hydrogen bonded into 4-connected sheets in an
identical connectivity to the isomeric compound 1, with subtle
differences in the lengths of the amide hydrogen bonds. The sheets
are oriented along the body diagonal of the unit cell. The crystals
contain no solvate molecules and thus the sheets are closely-
packed to complete the 3-D packing within the crystal.
The solid-state conformations for 1 and 2 are quite different to
those observed for a complex of compound A reported in the lit-
erature. In a [2þ2] dimetallomacrocycle reported by Diaz et al.17
compound A adopts a planar, more open conformation with one
amide NH and a second amide carbonyl group pointing into the
macrocyclic structure. This change apparently arises from switch-
ing the positions of the methylene and carbonyl groups within the
flexible arms of the diamides, although compound A is coordinated
by a metal in the work of Diaz et al.
2.2.3. Structures of N,N0-[1,4-phenylenebis(methylene)]-bis-4-
pyridinecarboxamide: 4$1/3(CD3COCD3) and 4$2(H2O)
Standing of an acetone-d6 solution of 4 provided needle-shaped
crystals suitable for X-ray crystallography. Compound 4 crystallises
in the rhombohedral space group R-3 with a hexagonal arrange-
ment of six molecules of the ligand around channels of disordered
acetone solvent. The asymmetric unit consists of half a ligand
molecule and a highly disordered, and partially occupied, acetone
solvate molecule lying on a special position. The complete ligand is
generated by a centre of symmetry and 4 adopts an almost identical
conformation to 3 but with slight twisting of the pyridyl rings
relative to the plane of the amide bonds (torsion angle of 31.6ꢀ
relative to the equivalent torsion angle for 3 of 4.9ꢀ). Each molecule
of 4 is involved in four hydrogen bonds; two bonds to two different
symmetry-related molecules resulting in a hydrogen bonded 1-D
tape (Fig. 7).
The packing of 4 in the high-symmetry rhombohedral space
group consists of rosettes of six 1-D hydrogen bonded tapes of 4
2.2.2. Structure of N,N0-[1,4-phenylenebis(methylene)]-bis-3-
pyridinecarboxamide 3
Crystals of 3 were obtained by slow evaporation of a methanol–
acetonitrile solution of the diamide and silver hexa-
fluorophosphate. Compound 3 crystallises in the monoclinic space
Figure 6. A perspective view of the four-connected 2-D hydrogen bonded network in
the structure of 3.
Figure 7. View of the hydrogen bonded tapes of 4 extending along the c-axis of the
unit cell.

C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
4685
Figure 10. A view of the 3-D hydrogen bonded network structure in the crystal
structure of 4$2(H2O) when viewed down the a-axis. Each 1-D tape is hydrogen
bonded to four other tapes through the water solvate molecules.
Figure 8. A perspective view of the packing of 4$1/3(CD3COCD3) viewed down the
c-axis of the unit cell, showing the rosettes of six 1-D hydrogen bonded tapes of 4
arranged around the channels of highly disordered acetone molecules (not shown).
molecules of 6 and a hydrogen bonded water molecule in the
asymmetric unit (Fig.11). The two molecules of 6 in the asymmetric
unit have very similar conformations, with the only differences
being subtle discrepancies in bond lengths and angles (particularly
in the intramolecular hydrogen bonding patterns) and an altered
intermolecular hydrogen bonding pattern. A solvate water mole-
cule acts as a hydrogen bond donor to one molecule of 6 through
a pyridyl ring nitrogen atom and an amide carbonyl oxygen atom
(on a symmetry equivalent molecule). The solvate water molecule
also acts as a hydrogen bond acceptor for a Cpy–H (d¼2.387 Å)
provided by the other molecule of 6 in the asymmetric unit.
Intramolecular hydrogen bonding (d¼2.250–2.369 Å) pre-orga-
nizes the NH functionality of the ligand into a central pocket,
hopefully capable of binding anions. This is the exact opposite of
the behaviour of compounds 1 and 2, based around the 1,3-xylene
core, whereby steric repulsions appear to force the amide func-
tional groups out of the plane of the xylene core. It also appears
there may also be weak C–H/O]C interactions (d¼2.456 and
2.471 Å) between the two molecules in the asymmetric unit.
Both of the molecules form hydrogen bonded dimers in the solid
state (Fig. 12). The hydrogen bonding motifs are the same for both
dimers but there are subtle differences in the hydrogen bond
lengths. The intermolecular NH/Npy hydrogen bonding distances
within the dimers range from 2.16 to 2.42 Å. One of the dimers has
an asymmetric hydrogen bonding arrangement with two shorter
and two longer hydrogen bonds, while the second dimeric as-
sembly has a hydrogen bonding pattern with near equivalent hy-
drogen bond lengths. The extensive hydrogen bonding interactions
arranged around the channels of disordered acetone molecules,
Figure 8. These rosette arrangements are stabilized by very weak C–
H/Npy interactions (d¼2.55 Å) between adjacent molecules of 4.
As an interesting comparison, a second sample of crystals of
compound 4 was obtained by slow evaporation of an acetonitrile–
methanol solution of 4 and silver trifluoroacetate. The compound is
a 3-D hydrogen bonded network structure, which crystallises in the
monoclinic space group P21/n. The compound crystallises as its
dihydrate, which appears to be a common formulation for similar
diamides.22,23 The water solvate molecules mediate the hydrogen
bonding between the molecules of 4. This leads to hydrogen
bonded one dimensional tapes with molecules of 4 connected by
two water molecules to a further molecule of 4 (Fig. 9) extending
along the a-axis of the unit cell. The water molecules act as three
connecting nodes forming three hydrogen bonds with three dif-
ferent molecules of 4. Within the tapes the OH/O]C hydrogen
bond distance is 2.123 Å, while the NH/Owater hydrogen bond
distance is 2.061 Å. The water solvate molecules are involved in
a third hydrogen bond as a donor to a pyridine nitrogen atom of
a nearby tape (OH/Npy d¼1.962 Å). This leads to a 3-D hydrogen
bonded network whereby each tape is hydrogen bonded, through
water solvate molecules, to four other tapes, Figure 10.
2.2.4. Structure of N,N0-2,6-bis(3-pyridylmethyl)pyridine
dicarboxamide hydrate, 6$H2O
Compound
6 was crystallised by slow evaporation of
a dichloromethane solution of the compound. Compound 6 crys-
tallises in the triclinic space group P-1, with two complete
Figure 11. A view of the asymmetric unit of 6$H2O, showing the pre-organizing in-
tramolecular hydrogen bonding interactions and the intermolecular hydrogen bonding
by one molecule of 6 to a solvate water molecule.
Figure 9. View of the water solvate-mediated hydrogen bonded tapes of 4 extending
along the a-axis of the unit cell of the structure of 4$2(H2O).

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C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
overlapping of the hydrogen bonded chains within the 2-D network
but no -stacking interactions are apparent between the central
p
pyridine rings of adjacent molecules of 7. The water molecule hy-
drogen bonded within the cavity of the diamide accepts two hy-
drogen bonds and is the donor in two other hydrogen bonds, while
the other water solvate molecule is three connecting (donor of two,
acceptor for one). The crystal packing is completed by weaker CH/
p
and
p-stacking interactions between the 2-D hydrogen bonded
sheets.
Within the seven diamide structures reported, a number of
different hydrogen bond motifs and diamide conformations have
been observed. Regarding this latter feature, in our investigation of
coordination complexes of these ligands30 we have observed that
these flexible diamides maintain similar conformations in the
resulting coordination polymers and discrete metallo-macrocyclic
structures. Thus, while the diamides have a number of degrees of
flexibility within their structures there are preferred conformations
for the various cores of the diamides that appear to restrict the
conformations.
Figure 12. One of the two hydrogen bonded dimers of 6, with only the intermolecular
hydrogen bonding shown. Symmetry operation used to generate dimer: ꢁxꢁ1, ꢁy, 1ꢁz.
On the former point of hydrogen bond motifs, the seven struc-
tures show several different hydrogen bonding patterns that have
been observed for other diamide ligands reported in the literature
(Fig. 15). Within the structures of 1$CDCl3 and 2, diamide hydrogen
bonding motifs (a) and (b) are observed; within the dimeric units
mode (b) occurs and the connections between dimeric units utilise
mode (a). Diamide 3 utilizes mode (a), while the structure of 4$1/
3(CD3COCD3) utilizes mode (b). Mode (b) is observed in the dihy-
drate of compound 4 but the hydrogen bonds are mediated by
water solvate molecules. The crystal structures of compounds 6 and
7 have a primary amide hydrogen bonding donor motif as shown
for structure (c), where the two donors hydrogen bond to a non-
amide acceptor.
Preliminary investigations of the reactions of compounds 1–5
with transition metal salts have given solid-state structures in
which the pyridyl donors coordinate the metal cation to form 1-D
and 2-D coordination polymers and the amide N–H and C]O
groups are then involved in extending these structures to 2-D and
3-D networks, respectively, through hydrogen bonding.30 The
compounds most suitable for generating complexes capable of
anion binding into a cavity formed within a metallo-supramolec-
ular assembly appear to be compounds 6 and 7 with the pre-or-
ganized pocket. Recent studies into the coordination chemistry of 6
between 6 and the solvate water molecule lead to an intricate and
complicated hydrogen bonded network within the crystal.
2.2.5. Structure of N,N0-2,6-bis(4-pyridylmethyl)pyridine
dicarboxamide dihydrate, 7$2(H2O)
Compound 7 also crystallises in the triclinic space group P-1, but
with only one molecule of the diamide in the asymmetric unit
(Fig. 13). One solvate water molecule acts as a hydrogen bond ac-
ceptor for the amide N–H donors of 7 (NH/O, d¼2.099 and
2.114 Å). The solvate water molecule also acts as a hydrogen bond
donor (OH/Npy d¼1.994 Å) to another symmetry-related molecule
of 7. This results in hydrogen bonded dimers {(7)2(H2O)2} within
the crystal structure (Fig. 14). Again, intramolecular hydrogen
bonding (d¼2.264–2.290 Å) pre-organizes the NH functionalities of
the diamide into a central pocket, hopefully capable of binding
anions. A second solvate water molecule is hydrogen bonded to the
carbonyl group of 7 (OH/OC d¼1.897 Å).
Within the crystal structure of 7$2(H2O) the hydrogen bonded
dimers {(7)2(H2O)2} are packed in chains through hydrogen
bonding OH/O]C mediated by the second solvate water mole-
cule. The resulting chains are then associated with adjacent chains
through the two water solvate molecules to give a hydrogen
bonded 2-D network. The hydrogen bonding leads to an
Figure 13. A perspective view of the asymmetric unit of 7$2(H2O), showing the in-
tramolecular hydrogen bonding that pre-organizes the amide NH binding pocket and
the two hydrogen bonded water solvate molecules.
Figure 14. A view of the 2-D hydrogen bonded sheets in the crystal structure of
7$2(H2O).

C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
4687
In the crystal structure of 6$H2O the diamide forms a hydrogen
bonded dimer (Fig. 12). Electrospray mass spectrometry (ES-MS) of
6 conducted in chloroform solution reveals peaks for [6þH]þ
(348.2, 100%), [(6)2þH]þ (694.6, 55%) and [(6)3þH]þ (1041.6, 37%).
Formation of the dimeric ion [(6)2þH]þ could be due to formation
of a dimer like that observed in the crystal structure, although other
possibilities exist. The trimer may involve hydrogen bonding by
a third molecule of 6 to a amide oxygen atom of the dimer
[(6)2þH]þ to give the species observed by ES-MS. ES-MS in meth-
anol led to the observation of three dominant species [6þH]þ
(348.2, 50%), [6þNa]þ (370.1, 30%) and [(6)2þNa]þ (716.8, 100%),
while the previously observed protonated dimer [(6)2þH]þ (694.6,
6%) was in low abundance and trimer [(6)3þH]þ was not observed.
The sodium salt of the trimer [(6)3þNa]þ (1063.7, 10%) could also be
detected. Similar observations were made for compound 7. ES-MS
in chloroform led to the ionization of only two species: [7þH]þ
(348.2, 100%) and [(7)2þH]þ (694.6, 34%). In methanol three main
species were observed, [7þH]þ (348.2, 100%), [7þNa]þ (370.1, 17%)
and [(7)2þNa]þ (716.8, 35%). The protonated dimer was also
detected with a low relative abundance. Compounds 6 and 7 did
not ionize very well in DMSO. The major peaks observed were due
to formation of [(6)2þNa]þ and [(7)2þNa]þ.
H
N
O
H
N
R
O
R
R
O
N
H
R
O
N
H
R
O
H
N
H
N
O
O
R
R
R
N
H
N
H
O
N
(a)
(b)
O
R
O
N
H
H
R
(c)
Figure 15. The simplified versions of the primary hydrogen bonding motifs observed
in the crystal structures reported in this work. The different conformations of the
various diamides are neglected.
We also examined the behaviour of 6 and 7 in solution by NMR
spectroscopy. Dilution experiments on both 6 and 7 in DMSO-d6,
where stable hydrogen bonded aggregates would be unlikely to be
observed, showed very little change in the spectra as the concen-
tration was lowered from ca. 0.5 M to 0.01 M. In contrast, over the
same regime of concentration the 1H NMR spectra of both 6 and 7
in CDCl3 showed quite dramatic changes with concentration
(Fig. 16). Significant downfield shifts for the NH protons were ob-
served in both cases as the concentration was increased. This in-
dicated hydrogen bonded aggregates were being formed in
solution. Upfield shifts were also observed, particularly for the
and 7 have revealed a number of discrete metallo-macrocyclic
structures and coordination polymers whereby the amide N–H
donor groups are hydrogen bonded to anions within these struc-
tures.30 The formation of these types of structures (involving hy-
drogen bonded anions) may be a consequence of the mismatch of
hydrogen bond donor acceptor and donor groups that limits the
ability to form the types of hydrogen bonded networks observed for
diamides like 1–5.
We examined the behaviour of compounds 6 and 7 in solution to
investigate if self-association could be mediated by hydrogen
bonding involving the central 2,6-pyridine dicarboxamide moiety.
Figure 16. The aromatic regions of the 1H NMR spectra of 6 (a) and 7 (b) in CDCl3.

4688
C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
pyridyl protons on the external pyridine rings but also for the H3
and H5 protons on the central 2,6-pyridine dicarboxamide core.
These changes are consistent with the formation of a hydrogen
bonded dimer in which adjacent aromatic rings (see Fig. 12) result
in shielding of the pyridyl protons on 6 (and 7 in solution).
literature procedures and freshly distilled as required. 2,6-Dime-
thylpyridine dicarboxylate was prepared by a literature method.31
4.2. Syntheses
4.2.1. General procedure for the synthesis of 1–4
3. Conclusions
Commercially available acid chloride hydrochloride salts
(20 mmol) were suspended in dichloromethane (20 mL) in a round
bottomed flask fitted with a pressure equalizing dropper funnel.
The dropping funnel was charged with dichloromethane (20 mL),
the diamine (10.0 mmol) and triethylamine (3.0 mL, 21.6 mmol),
which was then added dropwise to the suspension. The reaction
mixture was stirred at room temperature for 24–36 h before the
resulting suspension was poured into saturated sodium bi-
carbonate solution (300 mL) and extracted with dichloromethane
(3ꢂ200 mL). The combined extracts were dried over MgSO4 and the
dichloromethane removed. The resulting residue was purified as
described.
In summary, seven bis-pyridyl ligands were prepared in one
step from commercially available compounds in moderate to good
yields. Crystal structures of six of the diamide compounds are
reported, revealing information about the structures and confor-
mations of these diamides. While these structures only provide
information regarding the solid state, they provide some insight
into the type of compound more likely to give the required si-
multaneous cation and anion binding in solution. In this regard,
compounds 1–5 all display hydrogen bonded 1-D tapes and 2-D
sheet structures that utilise all the N–H donors in forming the
resulting network structure. This would appear to limit their ap-
plicability for simultaneous cation and, in particular, anion binding.
These extended network structures form through complementary
hydrogen bonding interactions whereby each molecule displays
two regions with hydrogen bond donors and two with hydrogen
bond acceptors. This contrasts with the type of solid-state struc-
tures observed with compounds 6 and 7. In these structures the
preorganised amide N–H hydrogen atoms are involved in hydrogen
bonding only to water solvate molecules (6) or the external pyri-
dine donor in the case of 7. In the case of these two compounds,
each molecule displays only one region with hydrogen bond donors
and two with hydrogen bond acceptors. This arrangement limits
the potential for the types of hydrogen bonded network observed
for 1–5 and suggests that these compounds will be more suitable
for interacting with both cations and anions as part of discrete
metallo-supramolecular assemblies and coordination polymers.
Unfortunately, the ease of crystallization of the hydrogen
bonded network structures of compounds 1–5 reported here, and
in other studies by us,30 indicates that hydrogen bonded networks
of the nature described for diamides but involving discrete co-
ordination complexes and infinite coordination polymers will be
ever present issues. As noted, some of the crystal structures
reported here were obtained from solutions containing transition
metal salts indicating a preference for forming hydrogen bonded
networks over metal complexes under the conditions employed to
crystallize these particular compounds.
4.2.2. N,N0-[1,3-Phenylenebis(methylene)]bis-3-
pyridinecarboxamide, 1
Following the general procedure a pink-brown oil was obtained.
This was triturated with hot diethyl ether, collected by filtration,
washed with diethyl ether to give the diamide 1 as a white solid
(2.70 g, 78%). Mp 141–142 ꢀC; Found: C, 69.3; H, 5.4; N 16.1.
C20H18N4O2 requires C, 69.3; H, 5.25; N 16.2%; max(KBr disk)/cmꢁ1
3356, N–H str. (asym.); 3062, N–H str. (sym.); 1633, C]O str.; 1594,
C]C str.; 1571, N–H bend and 1538, N–H bend (1ꢀ); 1H (500 MHz;
acetone-d6; Me4Si)
d
¼4.61 (4H, d, 3J¼5.8 Hz,
f-CH2NH), 7.28–7.29
(3H, m, H4, H5, H6), 7.41 (1H, s, H2), 7.45 (2H, dd, 3J¼4.8, 7.9 Hz,
pyH5), 8.23 (2H, dt, 3J¼7.9 Hz, pyH4), 8.43 (2H, br s, NH), 8.69 (2H,
d, 3J¼4.8 Hz, pyH6) and 9.09 (2H, d, 2J¼1.7 Hz, pyH2); 13C
(125 MHz; acetone-d6; Me4Si)
d¼43.9, 124.2, 127.2, 127.6, 129.4,
131.2, 135.6, 140.5, 149.4, 152.8 and 165.9; m/z (APCI) 347 (MHþ,
100%). Crystals of 1$CHCl3 were obtained from a concentrated
chloroform solution on standing.
4.2.3. N,N0-[1,3-Phenylenebis(methylene)]bis-4-
pyridinecarboxamide, 2
Following the general procedure described, but using
dichloromethane–methanol (98:2, 3ꢂ200 mL) to extract the
product from the aqueous bicarbonate solution, a white solid was
obtained. This was suspended in diethyl ether, collected by filtra-
tion, washed with diethyl ether to give the diamide 2 as a white
solid (2.05 g, 59%). Mp 177–178 ꢀC; Found: C, 68.7; H, 5.2; N 15.9.
C20H18N4O2$1⁄4 H2O requires C, 68.45; H, 5.3; N 16.0%; max(KBr
disk)/cmꢁ1 3307, N–H str. (asym.); 3062, N–H str. (sym.); 1646, C]O
str.; 1601, C]C str. and 1547, N–H bend; 1H (500 MHz; acetone-d6;
4. Experimental
4.1. General experimental
Me4Si)
d
¼4.60 (4H, d, 3J¼5.9 Hz,
f-CH2NH), 7.27–7.29 (3H, m, H4,
Melting points were recorded on an Electrothermal melting
point apparatus. Infrared spectra were collected on a Perkin Elmer
BX FTIR spectrometer as KBr disks. The Campbell Microanalytical
Laboratory at the University of Otago performed elemental analy-
ses. Electrospray (ES) mass spectra were recorded using a Finnigan
LCQ mass spectrometer. Other mass spectral analyses were carried
H5, H6), 7.39 (1H, s, H2), 7.78 (4H, d, 3J¼4.5 Hz, pyH3, pyH5), 8.51
(2H, br s, NH) and 8.70 (4H, d, 3J¼7.6 Hz, pyH2, pyH6); 13C
(125 MHz; acetone-d6; Me4Si)
d
¼43.8, 122.0, 127.2, 127.5, 129.4,
140.4, 142.6, 151.3 and 165.8; m/z (APCI) 347 (MHþ, 100%). Crystals
of 2 were obtained from slow evaporation of a methanol solution of
2 and copper nitrate.
out on a Shimadzu LCMS-QP8000a using an APCI ionization tech-
nique. NMR spectra were recorded on either a Varian Unity Inova
300 MHz, 500 MHz or Bruker 300 MHz NMR spectrometer at 23 ꢀC
using a 5 mm probe. 1H NMR spectra recorded in CDCl3 were ref-
erenced relative to the internal standard Me4Si; 1H NMR spectra
recorded in DMSO-d6 were referenced to the solvent peak: 2.6 ppm.
When required, 2-D COSY and NOESY experiments were performed
using standard pulse sequences. Unless otherwise stated, the values
given for chemical shifts are to the centre of a multiplet.
4.2.4. N,N0-[1,4-Phenylenebis(methylene)]bis-3-
pyridinecarboxamide, 3
Following the general procedure described, a white solid was
obtained after quenching the reaction with aqueous bicarbonate
solution. This was collected by filtration, washed with dichloro-
methane, ethanol and diethyl ether and dried under suction to give
3 (1.35 g, 39%). The filtrate was poured into a separating funnel, the
chlorinated layer separated and the aqueous layer extracted with
dichloromethane–methanol (95:5, 3ꢂ200 mL). The combined ex-
tracts were dried over MgSO4 and the solvent removed to give
Unless otherwise stated, reagents were obtained from com-
mercial sources and used as received. Solvents were dried by

C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
4689
a white solid. The solid was suspended in dichloromethane (ca.
10 mL), collected by filtration, washed with diethyl ether to give
further diamide 3 as a white solid (540 mg, 16%, combined yield
1.89 g, 55%). Mp 203.5–205.5 ꢀC; Found: C, 67.5; H, 5.2; N 15.5.
C20H18N4O2$1⁄2 H2O requires C, 67.6; H, 5.4; N 15.8%; max(KBr
disk)/cmꢁ1 3332, N–H str. (asym.); 3060, N–H str. (sym.); 1639, C]O
str.; 1592, C]C str. and 1542, N–H bend; 1H (500 MHz; acetone-d6;
were refluxed under nitrogen in toluene (20 mL) for 18 h. The so-
lution was cooled to room temperature and the solvent removed on
the rotary evaporator. The oily residue was dissolved in dichloro-
methane (75 mL), washed with saturated NaHCO3 solution
(2ꢂ50 mL), dried over MgSO4 and taken to dryness. This gave a pale
yellow oil that solidified on standing. The solid was suspended in
hot diethyl ether (10 mL), collected by filtration, washed with
a further quantity of diethyl ether (10 mL) and dried in vacuo to give
6 as a white solid (659 mg, 76%). Mp 164–166 ꢀC; Found: C, 64.4; H,
5.1; N 19.5. C19H17N5O2$1⁄2 H2O requires C, 64.0; H, 5.1; N 19.65%;
max(KBr disk)/cmꢁ1 3259, N–H str. (asym.); 3090, N–H str. (sym.);
1677, C]O str. and 1532, N–H bend (1ꢀ); 1H (500 MHz; CDCl3;
Me4Si)
d
¼4.60 (4H, d, 3J¼5.8 Hz,
f-CH2NH), 7.36 (4H, s, H2, H3, H5,
H6), 7.47 (2H, dd, 3J¼4.8, 7.9 Hz, pyH5), 8.25 (2H, dt, 3J¼7.9 Hz,
pyH4), 8.40 (2H, br s, NH), 8.69 (2H, d, 3J¼4.8 Hz, pyH6) and 9.10
(2H, d, 2J¼1.8 Hz, pyH2); 13C (125 MHz; acetone-d6; Me4Si)
¼43.8,
d
124.2, 128.7, 131.2, 135.6, 139.1, 149.4, 152.8 and 165.8; m/z (APCI)
347 (MHþ, 100%). Crystals of 3 were obtained from a methanol–
acetonitrile solution of 3 and silver hexafluorophosphate by slow
evaporation.
Me4Si)
d
¼4.47 (4H, d, 3J¼6.2 Hz, pyCH2NH), 7.18 (2H, dd, 3J¼4.8,
7.7 Hz, pyH50), 7.58 (2H, d, 3J¼7.8 Hz, pyH40), 8.09 (1H, t, 3J¼7.8 Hz,
pyH4), 8.19 (2H, d, pyH20), 8.43 (4H, m, pyH3, pyH5, pyH60) and 8.86
(1H, t, 3J¼6.0 Hz, NH); (500 MHz; acetone-d6; Me4Si)
¼4.62 (4H, d,
d
4.2.5. N,N0-[1,4-Phenylenebis(methylene)]bis-4-
pyridinecarboxamide, 4
3J¼6.1 Hz,
f
-CH2NH), 7.30 (2H, dd, 3J¼4.8, 7.8 Hz, pyH50), 7.71 (2H,
dt, J¼7.8, pyH40), 8.24 (1H, t, 3J¼6.9 Hz, pyH4), 8.36 (2H, d,
3
Following the general procedure described (on a smaller scale:
isonicotinoyl chloride hydrochloride 8.43 mmol; 1,4-xylenedi-
amine 4.15 mmol), a white solid was obtained after quenching the
reaction with aqueous bicarbonate solution. This was collected by
filtration, washed with dichloromethane, ethanol and diethyl ether
and dried under suction to give 4 (783 mg, 54%). The filtrate was
poured into a separating funnel, the chlorinated layer separated and
the aqueous layer extracted with dichloromethane–methanol (9:1,
4ꢂ100 mL). The combined extracts were dried over MgSO4 and the
solvent removed to give further 4 as an oily solid. This was sus-
pended in dichloromethane (ca. 10 mL) to give a white solid, col-
lected by filtration, washed with diethyl ether to give further
diamide 4 (527 mg, 37%; combined yield 1.31 g, 91%). Mp 197–
199 ꢀC; Found: C, 67.0; H, 5.3; N 15.6. C20H18N4O2$2/3H2O requires
C, 67.0; H, 5.45; N 15.6%; max(KBr disk)/cmꢁ1 3287, N–H str. (asym.);
3062, N–H str. (sym.); 1640, C]O str.; 1600, C]C str. and 1540, N–H
3J¼6.9 Hz, pyH3, pyH5), 8.46 (2H, d, 3J¼4.8 Hz, pyH60), 8.66 (2H, d,
pyH20) and 9.23 (2H, br s, NH); 13C (125 MHz; CDCl3; Me4Si)
d
¼40.7,
123.8, 125.5, 134.3, 136.0, 139.2, 148.7, 148.8, 148.9 and 163.9; m/z
(APCI) 348 (MHþ, 100%). Crystals were obtained by slow evapora-
tion of a dichloromethane solution of 6.
4.2.8. N,N0-2,6-Bis(4-pyridylmethyl)pyridine dicarboxamide 7
In a similar approach to the synthesis of 6, 2,6-dimethylpyridine
dicarboxylate (780 mg, 4.00 mmol) and a slight excess of 4-ami-
nomethylpyridine (1.12 mL, 11.0 mmol) were refluxed under ni-
trogen in toluene (30 mL) for 120 h. The solution was cooled to
room temperature and the solvent removed on the rotary evapo-
rator. The oily residue was dissolved in dichloromethane (100 mL),
washed with saturated NaHCO3 solution (2ꢂ50 mL), dried over
MgSO4 and taken to dryness. This gave a pale yellow oil that was
triturated with hot ethyl acetate, collected by filtration, washed
with diethyl ether (10 mL) and dried in vacuo to give 6 as a cream
solid (549 mg, 40%). Mp 142–3 ꢀC; Found: C, 65.7; H, 4.9; N 20.2.
C19H17N5O2 requires C, 65.7; H, 4.9; N 20.2%; max(KBr disk)/cmꢁ1
3260, N–H str. (asym.); 1761, C]O str. and 1533, N–H bend (1ꢀ); 1H
bend; 1H (500 MHz; acetone-d6; Me4Si)
d
¼4.59 (4H, d, 3J¼5.7 Hz,
f-
CH2NH), 7.35 (4H, s, H2, H3, H5, H6), 7.80 (4H, d, 3J¼4.5 Hz, pyH3,
pyH5), 8.48 (2H, br s, NH) and 8.71 (4H, d, 3J¼4.5 Hz, pyH2, pyH6);
13C (125 MHz; acetone-d6; Me4Si)
d
¼43.2, 121.4, 128.1, 138.4, 142.0,
150.7 and 165.2; m/z (APCI) 385 (MKþ, 100%), 369 (MNaþ, 22), 347
(MHþ, 90). Crystals of 4$1/3(CD3COCD3) were obtained from a con-
centrated acetone-d6 solution of 4 by slow evaporation, while
crystals of 4$2(H2O) were obtained from a solution of 4 and silver
trifluoroacetate dissolved in methanol and acetonitrile.
(300 MHz; CDCl3; Me4Si)
d
¼4.54 (4H, d, 3J 6.3 Hz, pyCH2NH), 7.03
(4H, d, 3J 5.9 Hz, H30, H50), 8.13 (1H, t, 3J 8.0 Hz, H4), 8.36 (4H, d, 3J
6.0 Hz, H20, H60), 8.46 (2H, d, 3J 6.0 Hz, H3, H5), 9.00 (2H, t, 3J 6.3 Hz,
NH); 13C (125 MHz; CDCl3; Me4Si)
d
¼42.1, 122.4, 125.6, 139.3, 147.6,
148.5, 149.6 and 164.0; m/z (ES-MS) 348.4 (MHþ, 100%). Crystals
were obtained by slow evaporation of an ethyl acetate solution of 7.
4.2.6. N,N0-Bis(3-pyridylmethyl)benzene-1,3-dicarboxamide, 5
In a similar approach to the syntheses of 1–4, phthaloyl chloride
(2.03 g, 10.1 mmol) was dissolved in dichloromethane (20 mL). 3-
Pyridylmethylamine (2.1 mL, 20.6 mmol) and triethylamine
(2.9 mL, 20.9 mmol) dissolved in dichloromethane (20 mL) were
added slowly and the resulting solution stirred for 48 h to give the
diamine 5 as a white solid (2.29 g, 65%) following work-up in the
usual manner. Mp 148–149 ꢀC; Found: C, 69.35; H, 5.3; N 16.5.
C20H18N4O2 requires C, 69.3; H, 5.25; N 16.2%; max(KBr disk)/cmꢁ1
3268, N–H str. (asym.); 3055, N–H str. (sym.); 1665, C]O str.; 1631,
C]C str.; 1579, N–H bend and 1541, N–H bend (1ꢀ); 1H (500 MHz;
4.2.9. N-6-[(3-Pyridylmethylamino)carbonyl]-2-pyridinecarboxylic
acid methyl ester 8
A suspension of 2,6-dimethylpyridine dicarboxylate (1.96 g,
10.0 mmol) and 3-aminomethylpyridine (1.00 mL, 10.0 mmol) was
refluxed in toluene (40 mL) for 24 h. The toluene was removed in
vacuo, the residue was redissolved in dichloromethane (100 mL),
washed with dilute hydrochloric acid (0.2 M, 2ꢂ50 mL) and the
dichloromethane layer discarded. The aqueous extract was neu-
tralized with sodium bicarbonate, extracted with dichloromethane
(3ꢂ50 mL), dried over sodium sulfate and the solvent removed in
vacuo. The resulting residue was purified by flash column chro-
matography on silica gel eluting with 1:9 methanol–CH2Cl2 to give
8 as an oil. Triturating the oil with hot diethyl ether gave a cream
solid (1.62 g, 59%). Mp 87 ꢀC; Found: C, 62.0; H, 4.9; N 15.5.
C14H13N3O3 requires C, 62.0; H, 4.8; N 15.5%; max(KBr disk)/cmꢁ1
3505 O–H str.; 3283, N–H str. (asym.); 1731,1661, C]O str. and 1533,
acetone-d6; Me4Si)
d
¼4.64 (4H, d, 3J¼5.7 Hz, pyCH2NH), 7.31 (2H,
dd, 3J¼4.8, 7.7 Hz, pyH5), 7.56 (1H, t, 3J¼7.8 Hz, H5), 7.78 (2H, dt,
3J¼7.8 Hz, pyH4), 8.07 (2H, d, 3J¼7.8 Hz, H4, H6), 8.42 (1H, t, H2),
8.46 (2H, d, 3J¼4.7 Hz, pyH6), 8.50 (2H, br s, NH) and 8.62 (2H, d,
pyH2); 13C (125 MHz; acetone-d6; Me4Si)
d
¼41.8,124.2,127.0,129.5,
130.8, 135.8, 135.9, 136.1, 149.3, 150.3 and 166.9; m/z (APCI) 347
(MHþ, 100%).
N–H bend (1ꢀ); 1H (300 MHz; CDCl3; Me4Si)
d
¼4.00 (3H, s, OCH3),
3
4.72 (2H, d, J¼6.3 Hz, pyCH2NH), 7.27 (1H, m, pyH50, overlapped
3
4.2.7. N,N0-2,6-Bis(3-pyridylmethyl)pyridine dicarboxamide 6
2,6-Dimethylpyridine dicarboxylate (489 mg, 2.50 mmol) and
a slight excess of 3-aminomethylpyridine (0.56 mL, 5.49 mmol)
with CHCl3), 7.73 (1H, d, J¼7.8 Hz, pyH40), 8.04 (1H, t, 3J¼7.8 Hz,
pyH4), 8.25 (1H, d, 3J¼7.8 Hz, pyH3 or pyH5), 8.43 (1H, d, 3J¼7.8 Hz,
pyH3 or pyH5), 8.55 (2H, m, pyH60, NH) and 8.65 (1H, s, pyH20); 13C

4690
C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
(125 MHz; acetone-d6; Me4Si)
d
¼40.9, 52.9, 123.5, 125.5, 127.4,
133.7, 135.6, 138.6, 146.5, 148.9, 149.2, 149.7, 163.6 and 164.8; m/z
(ES-MS) 272.1 (MHþ, 72%).
4.2.10. N-6-[(4-Pyridylmethylamino)carbonyl]-2-
pyridinecarboxylic acid methyl ester 9
A suspension of 2,6-dimethylpyridine dicarboxylate (3.92 g,
20.0 mmol) and 4-aminomethylpyridine (2.00 mL, 20.0 mmol) was
refluxed in toluene (80 mL) for 36 h. The toluene was removed in
vacuo, the residue was redissolved in dichloromethane (100 mL),
washed with dilute hydrochloric acid (0.2 M, 2ꢂ100 mL) and the
dichloromethane layer discarded. The aqueous extract was neu-
tralized with sodium bicarbonate, extracted with dichloromethane
(3ꢂ100 mL), dried over sodium sulfate and the solvent removed in
vacuo. The resulting residue was purified by flash column chro-
matography on silica gel eluting with 1:9 methanol–CH2Cl2 to give
9 as an oil, which solidified on standing. The solid was sonicated in
diethyl ether, collected by filtration and dried to give a cream solid
(3.71 g, 68%). Mp 129–30 ꢀC; Found: C, 62.0; H, 4.9; N 15.5.
C14H13N3O3 requires C, 62.1; H, 4.9; N 15.6%; max(KBr disk)/cmꢁ1
3284, N–H str. (asym.); 1712, 1673, C]O str.; 1600, N–H bend and
1561, N–H bend (1ꢀ); 1H (300 MHz; CDCl3; Me4Si)
d
¼4.01 (3H, s,
OCH3), 4.72 (2H, d, 3J¼6.5 Hz, pyCH2NH), 7.28 (overlapped with
residual CHCl3, 2H, m, pyH30, pyH50), 8.05 (1H, t, 3J¼7.8 Hz, pyH4),
8.27 (1H, d, 3J¼7.8 Hz, pyH5), 8.43 (1H, d, 3J¼7.8 Hz, pyH3) and 8.57
(3H, m, pyH20, pyH60, NH); 13C (125 MHz; CDCl3; Me4Si)
d
¼42.3,
53.0, 122.3, 125.6, 127.6, 138.7, 146.6, 147.1, 149.6, 150.0, 150.1 and
163.8; m/z (APCI) 272 (MHþ, 100%).
4.2.11. N,N0-20-Propyl-6-(3-pyridylmethyl)pyridine
dicarboxamide, 10
A solution of 8 (271 mg, 1.00 mmol) and propylamine (0.41 mL,
5.0 mmol) was heated in toluene (10 mL) at 45 ꢀC for 96 h. After
24 h further propylamine (0.41 mL, 5.0 mmol) was added. The so-
lution was evaporated to dryness to give a residue that was dis-
solved in dichloromethane (50 mL), washed with water (50 mL),
brine (50 mL), dried over sodium sulfate and the chlorinated sol-
vent removed on the rotary evaporator. The oily solid was triturated
with hot diethyl ether, the resulting cream solid collected by fil-
tration, washed with further diethyl ether and dried in vacuo to
give 8 (202 mg, 68%). Mp 118–20 ꢀC; Found: C, 63.3; H, 6.1; N 18.5.
C16H18N4O2$1⁄4 H2O requires C, 63.4; H, 6.2; N 18.5%; max(KBr
disk)/cmꢁ1 3308, N–H str. (asym.); 2962, 2933, C–H str.; 1677, C]O
str.; 1603, C]C str.; 1532, N–H bend; 1H (300 MHz; CDCl3; Me4Si)
d
¼0.94 (3H, t, 3J¼7.4 Hz, CH3), 1.62 (overlapped with water, 2H,
CH2CH2CH3), 3.41 (2H, q, 3J¼6.3, 7.9 Hz, CH2CH2NH), 4.71 (2H, d,
3J¼6.3 Hz, pyCH2NH), 7.29 (overlapped with residual CHCl3, 1H,
3
pyH50), 7.74 (1H, d, J¼7.8 Hz, pyH40), 7.83 (1H, br s, CH2CH2NH),
8.06 (1H, t, 3J¼7.9 Hz, pyH4), 8.24 (1H, br s, pyCH2NH), 8.39 (2H, m,
pyH3, pyH5), 8.55 (2H, m, pyH2, pyH6); 13C (125 MHz; CDCl3;
Me4Si)
d
¼11.4, 22.9, 40.8, 41.2, 123.8, 125.1, 125.3, 134.1, 135.9, 139.1,
148.3, 148.9, 149.0, 149.2, 163.5 and 163.9; m/z (ES-MS) 299.2 (MHþ,
92%), 321.1 (MNaþ, 14%).
4.2.12. N,N0-20-Propyl-6-(4-pyridylmethyl)pyridine
dicarboxamide, 11
A solution of 9 (271 mg, 1.00 mmol) and propylamine (0.41 mL,
5.0 mmol) in toluene was heated at 45 ꢀC for 96 h. After 24 h
further propylamine (0.41 mL, 5.0 mmol) was added. The solution
was evaporated to dryness to give a residue that was dissolved in
dichloromethane (50 mL), washed with water (50 mL), brine
(50 mL), dried over sodium sulfate and the chlorinated solvent
removed on the rotary evaporator. Purification by flash column
chromatography on silica gel eluting with 1:9 methanol–
dichloromethane gave an oil. Triturating the oil with hot diethyl
ether gave 11 as a cream solid (173 mg, 58%). Mp 122–3 ꢀC;

C.J. Sumby, L.R. Hanton / Tetrahedron 65 (2009) 4681–4691
4691
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Found: C, 64.4; H, 6.3; N 18.8. C16H18N4O2 requires C, 64.4; H, 6.1;
N 18.8%; max(KBr disk)/cmꢁ1 3505 O–H str.; 3288, N–H str.
(asym.); 2956, 2932, C–H str.; 1665, C]O str.; 1533, N–H bend; 1H
(300 MHz; CDCl3; Me4Si)
d
¼0.96 (3H, t, 3J¼7.3 Hz, CH3), 1.63
(overlapped with water, 2H, CH2CH2CH3), 3.42 (2H, q, 3J¼6.3,
8.0 Hz, CH2CH2NH), 4.72 (2H, d, 3J¼6.4 Hz, pyCH2NH), 7.24 (1H, d,
3J¼5.9 Hz, pyH30, pyH50), 7.88 (1H, br s, CH2CH2NH), 8.08 (1H, t,
3J¼7.8 Hz, pyH4), 8.25 (1H, br s, pyCH2NH), 8.41 (2H, m, pyH3,
pyH5), 8.55 (2H, d, 3J¼5.9 Hz, pyH2, pyH6); 13C (125 MHz; CDCl3;
Me4Si)
d
¼11.4, 22.9, 41.3, 42.2, 122.3, 125.2, 125.5, 139.1, 147.5,
148.2, 149.2, 149.8, 163.4 and 164.0; m/z (ES-MS) 299.0 (MHþ,
30%), 321.7 (MNaþ, 14%).
4.3. X-ray crystallography
Crystals were mounted under oil on a glass fibre and X-ray
diffraction data collected at 90(2) K with Mo
Ka radiation
(
l¼0.71073 Å) using a Bruker-AXS Single Crystal Diffraction Sys-
tem fitted with an Apex II CCD detector. Data sets were corrected
for absorption using a multi-scan method, and structures were
solved by direct methods using SHELXS-9732 and refined by full-
matrix least squares on F2 by SHELXL-97,33 interfaced through the
program X-Seed.34 In general, all non-hydrogen atoms were re-
fined anisotropically and hydrogen atoms were included as in-
variants at geometrically estimated positions, unless specified
otherwise in additional details below. Details of data collections
and structure refinements are given in Table 1. CCDC-705849 to
705855 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Acknowledgements
C.J.S. acknowledges the Australian Research Council for an
Australian Post-Doctoral Fellowship and supporting this research
through a Discovery Project (DP0773011) and the University of
Adelaide for Faculty of Sciences Strategic Funding. The authors also
acknowledge the New Zealand Foundation for Research Science
and Technology for initially supporting this research. The Univer-
sity of Otago is acknowledged for providing access to facilities for
X-ray crystallography.
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