1,8-Naphthyridinecarbaldehydes and Their Methyl-Substituted Precursors: Synthesis, Molecular Structures, Supramolecular Motifs and Trapped Water Clusters

Article abstract of DOI:10.1002/ejoc.201701193

1,8-Naphthyridinecarbaldehydes bearing chlorine, pyrrolidinyl, piperidinyl or morpholinyl groups, were synthesised by oxidation of their methyl-substituted precursors. The prepared carbaldehydes represent valuable starting materials for the construction of systems that are useful for supramolecular and medicinal chemistry. Single-crystal X-ray diffraction studies of four carbaldehydes and six methyl derivatives provided interesting information about the supramolecular motifs in the crystal structures of solvent-free and solvated naphthyridines. The formation of interesting water clusters, for example, T4(2) water tape, was observed in the case of 7-methyl-2-(piperidin-1-yl)-1,8-naphthyridine as well as in the crystal structure of a by-product 7-(morpholin-1-yl)-1,8-naphthyridine-2-carboxylic acid. Knowledge of the detailed structural properties of water clusters is of great research interest to a broad range of scientific disciplines.

Full text of DOI:10.1002/ejoc.201701193

DOI: 10.1002/ejoc.201701193
Full Paper
Supramolecular Systems
1,8-Naphthyridinecarbaldehydes and Their Methyl-Substituted
Precursors: Synthesis, Molecular Structures, Supramolecular
Motifs and Trapped Water Clusters
Robert Rosin,[a] Wilhelm Seichter,[a] Anke Schwarzer,[a] and Monika Mazik*[a]
Abstract: 1,8-Naphthyridinecarbaldehydes bearing chlorine, in the crystal structures of solvent-free and solvated naphthyr-
pyrrolidinyl, piperidinyl or morpholinyl groups, were synthe- idines. The formation of interesting water clusters, for example,
sised by oxidation of their methyl-substituted precursors. The T4(2) water tape, was observed in the case of 7-methyl-2-(piper-
prepared carbaldehydes represent valuable starting materials idin-1-yl)-1,8-naphthyridine as well as in the crystal structure of
for the construction of systems that are useful for supramolec- a by-product 7-(morpholin-1-yl)-1,8-naphthyridine-2-carboxylic
ular and medicinal chemistry. Single-crystal X-ray diffraction acid. Knowledge of the detailed structural properties of water
studies of four carbaldehydes and six methyl derivatives pro- clusters is of great research interest to a broad range of scien-
vided interesting information about the supramolecular motifs tific disciplines.
Introduction
betic, antihypertensive, fungicidal and other activities.[1a,3] The
1,8-naphthyridine unit has also proved to be a valuable building
Among the known naphthyridines (isomeric pyridopyridines), block for a range of artificial receptors,[4] hydrogen-bonded
1,8-naphthyridine derivatives have attracted most attention assemblies and other supramolecular systems.[5,6] The syntheses
because of their interesting biological and chemical proper- of diverse 1,8-naphthyridine derivatives and the investigation
ties.[1–3] Representatives of this class of compounds have been of their properties have been the subject of intense research
recognised as anti-infective agents (antibacterial and antiviral) over a long period of time and the results of these studies are
as well as substances with analgetic, anti-inflammatory, antidia- the focus of books[2] and review articles.[1]
Figure 1. Structures of 1,8-naphthyridine carbaldehydes 1–8 and of the methyl-substituted precursors 9–16.
Our previous studies showed the usefulness of various het-
erocyclic aldehydes (such as imidazole-, indole-, pyrrole-, pyrid-
ine-, pyrazole- and quinolinecarbaldehydes) in the syntheses of
supramolecular systems,[7,8] including artificial receptors for
ionic and neutral carbohydrates.[7] To realise an effective
synthesis of new 1,8-naphthyridine-bearing receptors, we were
interested in a simple synthetic access to substituted 1,8-
[a] Institut für Organische Chemie, Technische Universität Bergakademie
Freiberg,
Leipziger Strasse 29, 09599 Freiberg, Germany
E-mail: monika.mazik@chemie.tu-freiberg.de
http://tu-freiberg.de/fakultaet2/orgch
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201701193.
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naphthyridine-2-carbaldehydes. Such compounds are also valu- substituted derivative 9. By using this procedure, we could pre-
able targets for investigating their ability to participate in supra- pare compound 9 with 85 % yield from 21 (48 % overall yield
molecular motifs, especially hydrogen-bond patterns. This pa- from 2,6-diaminopyridine). The direct oxidation of 9 with selen-
per describes the preparation of new representatives of this ium(IV) oxide (SeO2) in 1,4-dioxane[15] provided 7-chloro-1,8-
class of compounds (compounds 1–8, Figure 1) as well as naphthyridine-2-carbaldehyde (1) in 56 % yield. To prepare
single-crystal X-ray diffraction studies that allowed detailed carbaldehydes 2–4, compound 9 was treated with pyrrolidine
packing analysis of carbaldehydes 2–4 and 6. The target 1,8- (22), piperidine (23) and morpholine (24) to give 7-methyl-2-
naphthyridinecarbaldehydes 1–8, bearing chlorine, piperidinyl, (pyrrolidin-1-yl)-1,8-naphthyridine (10), 7-methyl-2-(piperidin-1-
pyrrolidinyl and morpholinyl groups, were synthesised by oxid- yl)-1,8-naphthyridine (11) and 7-methyl-2-(morpholin-4-yl)-1,8-
ation of their methyl-substituted precursors 9–16 (Figure 1). X- naphthyridine (12), respectively, in 86, 89 and 91 % yield. The
ray diffraction studies of the latter compounds have also been subsequent oxidation of compounds 10–12 with SeO2 provided
the subject of this work and provided interesting information the corresponding carbaldehydes 7-(pyrrolidin-1-yl)-1,8-
about the supramolecular motifs in the crystal structures of naphthyridine-2-carbaldehyde
(2),
7-(piperidin-1-yl)-1,8-
solvent-free and solvated naphthyridines (crystal structures of naphthyridine-2-carbaldehyde (3) and 7-(morpholin-4-yl)-1,8-
10–15). In addition, the crystal structure of a by-product, 7- naphthyridine-2-carbaldehyde (4) in 63, 71 and 55 % yield, re-
(morpholin-1-yl)-1,8-naphthyridine-2-carboxylic acid (17), could spectively.
also be obtained and analysed in the course of this work. The
formation of interesting water clusters, for example T4(2) water
tape, was observed in the case of 7-methyl-2-(piperidin-1-yl)-1,8-
As shown in Scheme 1, the synthesis of carbaldehydes 5–8
started from 2-amino-6-methylpyridine (25), which was con-
verted into 2,4-dihydroxy-3,7-dimethylnaphthyridine (27) by re-
naphthyridine (11) and the by-product 17. As underlined in a
previous publication, “the exploration of structural and binding
properties of small water complexes provides a key for under-
standing bulk water in its liquid and solid phase and for under-
standing solvation phenomena”.[9a] Given the fundamental im-
portance of water in biological, chemical and physical proc-
esses, various water clusters have been extensively studied both
experimentally and theoretically,[9–12] and it should be noted
that the providing of detailed structural data of various
hydrogen-bonded water networks in diverse environments is
still the subject of intense research.
action with diethyl 2-methylmalonate (26) by following the pro-
cedure described by Ferrarini et al.[14] Treatment of 27 with
POCl3 provided 2,4-dichloro-3,7-dimethyl-1,8-naphthyridine
(13), which was either directly oxidised with SeO2 to give the
carbaldehyde
5
(5,7-dichloro-6-methyl-1,8-naphthyridine-2-
carbaldehyde, 30 % yield) or converted into the 4-chloro-3,7-
dimethyl-2-(piperidin-1-yl)-1,8-naphthyridine (14) by reaction
with piperidine (77 % yield). 5-Chloro-6-methyl-7-(piperidin-1-
yl)-1,8-naphthyridine-2-carbaldehyde (6) could then be ob-
tained by oxidation of 14 with SeO2 in 65 % yield.
To prepare 6-methyl-5,7-di(piperidin-1-yl)-1,8-naphthyridine-
2-carbaldehyde (7) and 6-methyl-5-(morpholin-4-yl)-7-(1-piper-
idinyl)-1,8-naphthyridine-2-carbaldehyde (8), compound 14 was
converted into 3,7-dimethyl-2,4-di(piperidin-1-yl)-1,8-naphthyr-
idine (15) and 3,7-dimethyl-4-(morpholin-4-yl)-2-(piperidin-1-
yl)-1,8-naphthyridine (16) by reaction with piperidine and
morpholine, respectively, in a sealed tube at 160 °C. In compari-
son to reported procedures,[14] the yield of 15 could be im-
proved from 10 to 42 % by an extension of the reaction time
and by introducing a slight variation of the purification process.
The oxidation of 15 and 16 with SeO2 yielded the target carb-
aldehydes 7 and 8 in 90 and 55 % yield, respectively.
Among the prepared target compounds 1–16, eleven com-
pounds, 1–8 and 10–12, have not previously been described.
Results and Discussion
Synthesis of Compounds 1–16
It is well known that 2-aminopyridine and its substituted deriva-
tives are valuable starting materials for the construction of the
1,8-naphthyridine scaffold, and their reactions with various re-
actants, such as ꢀ-keto esters or dicarboxylic esters, have pro-
vided a wide range of 1,8-naphthyridine derivatives.[1] We have
also used this strategy and started from commercially available
2,6-diaminopyridine and 2-amino-6-methyl-pyridine to prepare
2-chloro-7-methyl-1,8-naphthyridine (9) and 2,4-dichloro-3,7-di-
methyl-1,8-naphthyridine (13), which have been the basis for
the synthesis of the target carbaldehydes 1–8, as shown in
Scheme 1. The preparation of compounds 9 and 13 were car-
ried out according to the procedures reported by Brown[13] and
Ferrarini et al.,[14] respectively. The procedure described by
Brown[13] comprises the synthesis of 2-amino-7-methyl-1,8-
naphthyridine (20) by reaction of 2,6-diaminopyridine (18) with
Single crystals suitable for X-ray diffraction experiments
could be obtained for compounds 2–4, 6 and 10–15 by crystal-
lisation from ethyl acetate (in the case of 6), dioxane (2 and
13), tetrahydrofuran (in the case of 10), toluene (14) or a sol-
vent mixture such as methanol/water (3 and 15), ethanol/water
(4 and 11) or hexane/chloroform (12). X-ray diffraction experi-
ments provided crystal structures for solvent-free 2–4, 6, 10
and 12–14 as well as the hydrates 11·2H2O, 15·H2O and 17·H2O
(2:3.5) [crystal structure of a by-product]. Crystallographic data
and selected refinement parameters of the crystal structures are
summarised in Table S1 (see the Supporting Information). The
supramolecular motifs observed in the crystal structures as well
as the kind of the arrangement of water molecules in the
3-oxobutyraldehyde dimethylacetal (19) followed by conversion hydrates (the type of the water cluster) are described below
of 20 into 2-hydroxy-7-methyl-1,8-naphthyridine (21), which is (detailed information regarding all non-covalent interactions in
then treated with phosphoryl chloride (POCl3) to give chloro- the crystals is given in Tables S2–S6).
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Scheme 1. Syntheses of 1,8-naphthyridine carbaldehydes 1–8 and of the methyl-substituted precursors 9–16 (pyr = pyrrolidinyl, pip = piperidinyl and morph =
morpholinyl substituents). Reagents and conditions: (a) H3PO4, 3 h, 90 °C (77 % of 20);[13] (b) H2SO4, NaNO2, 80 °C (74 % of 21); (c) POCl3, 4 h, reflux (85 % of
9, 93 % of 13); (d) corresponding amine (4 equiv.), toluene, 6 h, reflux (86 % of 10, 89 % of 11, 91 % of 12, 77 % of 14); (e) SeO2,[15] 1,4-dioxane, 50 °C (55–
71 % yield in the case of 1–4, 30–90 % yield in the case of 5–8); (f) 26 (1 equiv.), Downterm A, 4 h, reflux (52 % of 27);[14] (g) sealed tube, 20 h, 160 °C (42 %
of 15, 25 % of 16).
Crystal Structures of 1,8-Naphthyridine-2-carbaldehydes
2–4 and 6
ring in 4 have an almost ideal chair geometry, whereas the
pyrrolidine ring in 2 displays an undistorted envelope confor-
mation (see also Figure S1 in the Supporting Information).
The carbaldehydes crystallise in the space groups C2/c (2), P1¯
The fact that the compounds reveal different space group
(3), Pca21 (4) and P21/c (6), each containing one molecule in symmetries suggests differences regarding the packing behav-
the asymmetric part of the unit cell. As can be seen from the iour of the molecules and the modes of noncovalent intermo-
ORTEP diagrams in Figure 2, the molecular structures are simi- lecular bonding. One-dimensional molecular ribbons extending
lar. In all cases, the formyl oxygen points away from the lone parallel to the crystallographic (012)-plane represent the basic
electron pair of the nitrogen atom N1 with torsion angles be- supramolecular aggregates of the crystal structure of 2. As de-
tween 169.2(1)° and 176.6(4)° (anti) for the atomic sequences picted in Figure 3a, the formyl groups of inversion related mol-
N1–C1–C9–O1. The bond length of N3–C7 (N3: pyrrolidine, ecules form a cyclic pattern of C–H···O hydrogen bonds of the
2
piperidine or morpholine nitrogen), which ranges from 1.352(1) graph set R2 (6).[16,17] In addition, the formyl oxygen atom par-
2
(2) to 1.388(2) Å (6) indicate a partial double bond character ticipates in a second supramolecular motif, R2 (10), with an aryl
(for information about the influence of the substituents on the hydrogen atom of a neighbouring molecule acting as a donor.
bond lengths, see the Supporting Information). The dihedral The H···O distances of 2.53 Å and 2.68 Å are shorter than the
angles between the plane of the naphthyridine moiety and that sum of van der Waals radii[18] of the involved atoms (2.72 Å).
defined by the formyl group are between 4.5(2)° (3) and 10.8(1)° The pattern of the intermolecular interactions is completed by
(2). The piperidine ring in 3 and 6 as well as the morpholine
C
aryl–H···N contacts,[19] which are slightly longer (see Figure 3a)
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Figure 2. Perspective views of the molecular structures of 2–4 and 6 including the atom numbering scheme. The thermal ellipsoids of the non-hydrogen
atoms are drawn at the 50 % probability level.
than the sum of van der Waals radii (2.75 Å for H and N), indicat-
ing the weak character of these interactions.
The crystal structure of the piperidinyl-substituted analogue
(compound 3) differs fundamentally from that of 2. The crystal
of 3 is constructed from infinite strands of C–H···O bonded mol-
ecules. Furthermore, the molecules of inversion related chains
are associated through π···π arene[20,21] (face-to-face) interac-
tions to form double strand-like aggregates, as illustrated in
Figure S2. The centroid···centroid (Cg···Cg) distance of interact-
ing aromatic rings is 3.649(2) Å.
In the crystal structure of 7-(morpholin-4-yl)-1,8-naphthyr-
idine-2-carbaldehyde (4), the presence of an additional ac-
ceptor atom (O2, morpholine oxygen) connects the molecules
to a three-dimensional supramolecular network. As shown in
Figure S3, the formyl oxygen atom is associated with a mor-
pholine hydrogen of a neighbouring molecule [d(H···O) 2.53 Å],
whereas the morpholine oxygen atom is involved in C–H···O
bonding with a naphthyridine hydrogen of an adjacent mol-
ecule acting as a donor [d(H···O) 2.54 Å]. Moreover, π···π arene
stacking[20,21] forces with Cg···Cg distances of 3.800(2) and
4.022(2) Å stabilise the crystal in the direction of the crystallo-
graphic a-axis.
The crystal structure of carbaldehyde 6 is constructed of
inversion symmetric molecular dimers held together by
Caryl–H···O hydrogen bonds [d(H···O) 2.56 Å], which create a su-
2
pramolecular ring motif of the graph set R2 (10) (see Figure 3b).
The molecular dimers are arranged in a stacking mode along
the crystallographic a-axis. In this stacking arrangement, con-
Figure 3. Packing diagrams of 2 (a) and 6 (b) including the numbering of
relevant atoms. Nitrogen atoms are displayed as cross-hatched (blue), oxygen
atoms as dotted (red) and chlorine atoms as hatched (green) circles. Broken
secutive dimers are displaced such that their ten-membered
hydrogen bonded rings are located between the naphthyridine
moieties of neighbouring molecules, which suggests attractive
forces between them. They comprise π···π interactions [Cg···Cg
3.765(1) Å] between aromatic rings as well as C=O···π con-
tacts[22] [d(O···Cg) 3.433(1) Å]. Clearly, a hydrogen bonded ring
lines represent hydrogen bonds, broken double lines indicate π···π arene
interactions. In (a), particular ring systems of intermolecular interactions,
R22(6) and R22(10), are specified by colour highlighting, whereas in (b) the
ring system R22(10) is specified. The following C–H···O/N interactions (H···O/
N distance) are shown: (a) Caryl–H···O=C (a = 2.53 Å), Cformyl–H···O=C (b =
2.68 Å), Caryl–H···N (c = 2.93 Å) and Caryl–H···N (d = 2.88 Å); (b) Caryl–H···O=
CH (2.56 Å) and π–π-stacking interactions (Cg···Cg distance: b = 3.76 Å).
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Figure 4. Schematic representations of the hydrogen-bond patterns in the crystal structures of carbaldehydes 2–4 and 6.
system featuring π-electrons can replace an aromatic ring in asymmetric unit, whereas the crystal structure of 14 was solved
this specific stacking arrangement.
in the triclinic space group P1¯ with two crystallographically in-
dependent, but conformationally similar molecules in the asym-
metric part of the unit cell. Perspective views of the molecular
structures are displayed in Figure 5. Possibly because of crystal
packing effects, the naphthyridine moiety of the molecules de-
viate slightly from planarity with maximum atomic distances
from the least-squares plane being 0.032(1) and –0.029(1) Å for
C7A and C6A of compound 14.
Schematic representations of the hydrogen-bond patterns in
the crystal structures of carbaldehydes 2–4 and 6 are given in
Figure 4.
Crystal Structures of Methyl-Substituted 1,8-
Naphthyridines 10 and 12–14
Naphthyridines 10, 12 and 13 crystallise in the monoclinic crys-
View of the crystal structure of 10 along the ac-plane reveals
tal system (space groups P21/c, P21/n) with one molecule in the a typical layer arrangement of molecules. An excerpt of the
Figure 5. ORTEP diagrams of the molecular structures of 10 and 12–14 including the atom numbering scheme. The thermal ellipsoids of non-hydrogen atoms
are drawn at the 50 % probability level.
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Figure 6. Packing diagrams of 10 (a) and 12 (b) including the numbering of relevant atoms. Nitrogen atoms are displayed as cross-hatched (blue), oxygen
atoms as dotted (red) circles; broken lines represent hydrogen bonds and broken double lines indicate π···π arene interactions. The following C–H···N/O
interactions (H···O/N distance) are shown: (a) Cpip–H···N (a = 2.74 Å) and Caryl–H···N (b = 2.92, c = 2.83 Å); (b) Cmorph–H···N (a = 2.70 Å) and Caryl–H···O (b =
2.41 Å).
packing structure is shown in Figure 6a. The molecular associa- connect the molecular chains into two-dimensional sheets ex-
tion via hydrogen bonding is restricted to weak C–H···N interac- tending parallel to the crystallographic (101)-direction. The lo-
tions [d(H···N) 2.74–2.92 Å]. The displacement between the mol- cation of the chloro substituents above the aromatic rings of
ecules of consecutive layers prevent effective π···π arene stack- neighbouring molecules and their distances of 3.382(1)–
ing. Instead, interlayer association is accomplished by C–H···π 3.531(1) Å (C–Cl···Cg) to the ring centres indicate the presence
contacts [d(H···Cg) 2.74 Å].
of C–Cl···π interactions.[26]
The introduction of a morpholinyl group, as in 12, induces a
crystal packing (Figure 6b) that differs considerably from that
of 10. The crystal structure consists of infinite twisted strands
of Carene–H···O bonded molecules [d(H···O) 2.41 Å] running
along the crystallographic 101 direction, while C–H···N
hydrogen bonds [d(H···N) 2.88 Å] and C–H···π contacts[23]
[d(H···Cg) 2.82 Å] connect the strands among each other.
In the crystal of the piperidinyl-substituted compound 14,
independent molecules are involved in a different way of inter-
molecular noncovalent bonding. As is clear from Figure 7b, one
of the molecules is associated through π···π stacking [Cg···Cg
3.690(1) Å] to form an inversion symmetric dimer. The chlorine
atoms of this dimer are excluded from intermolecular interac-
tions. The second molecule lacks stacking interactions. Its
Taking into account hydrogen bonding as the dominating chlorine atom, however, is used for formation of a C–H···Cl
intermolecular interaction, the crystal structure of 2,4-dichloro- hydrogen bond [d(H···Cl) 2.94 Å]. A variety of interactions com-
3,7-dimethyl-1,8-naphthyridine (13) is constructed of chains of prising C–H···N [d(H···N) 2.46–2.81 Å] and C–H···π contacts
C–H···N bonded molecules (Figure 7a). Weak Type I Cl···Cl inter- [d(H···Cg) 2.65–2.99 Å] link the molecules to a three-dimen-
actions[24,25] [d(Cl···Cl) 3.618(2) Å, θ1 = 140.1(1)°, θ2 = 125.8(1)°] sional supramolecular architecture.
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Figure 7. Excerpts of the packing structures of 13 (a) and 14 (b) including the numbering of relevant atoms. Nitrogen atoms are displayed as cross-hatched
(blue) and chlorine atoms as hatched (green) circles; broken lines represent hydrogen bonds and broken double lines π···π arene interactions. The following
interactions are shown: (a) Caryl–H···N (a = 2.54 Å, H···N distance) and C–Cl···Cl (b = 3.61 Å, Cl···Cl distance); (b) Caryl–H···N (a = 2.46 Å, H···N distance).
Hydrates of Compounds 11 and 15, and By-product 17
[7-(Morpholin-4-yl)-1,8-naphthyridine-2-carboxylic Acid]
centrosymmetric orthorhombic space group P212121 with one
molecule of the naphthyridine and two water molecules in the
asymmetric part of the unit cell (Figure 8).
Crystals of 11, obtained from an EtOH/H2O solvent mixture,
The most interesting feature of the crystal structure can be
turned out to be a hydrate,[11d,27] which crystallises in the non- seen in the formation of infinite corrugated tapes of hydrogen-
Figure 8. Molecular structures of 11 2 H2O, 15·H2O and 17·H2O (2:3.5; O7 is located on the symmetry axis) including the atom numbering scheme. The
thermal ellipsoids of non-hydrogen atoms are drawn at the 50 % probability level. Broken lines represent hydrogen bonds.
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Figure 9. (a) Packing diagram of 11·2H2O viewed down the crystallographic a-axis and (b) packing excerpt showing the self-assembly of water molecules
within the T4(2) tape. Nitrogen atoms are displayed as cross-hatched (blue) and oxygen atoms as dotted (red) circles. Broken lines represent hydrogen bonds,
broken double lines indicate π···π arene interactions. The following O–H···O/N interactions (H···O/N distance) are shown: O–H···N (a = 1.94 Å, H···N distance),
O–H···O (b = 2.01 Å, c = 2.05 Å, d = 1.98 Å). (c) Schematic representation of the T4(2) water tape.
bonded water molecules, which are accommodated in channel- ref.[10f]). In a few cases, the T4(2) water type has been known
like lattice voids extending along the crystallographic a-axis as a part of other infinite tapes; for example, as T4(2)6(2)[10h] or
(Figure 9). The channels of the host lattice adopt a nearly rec- T4(2)10(2) [results of a search for the T4(2) motif on CSD are
tangular cross-section with dimensions of ca. 7.9 × 5.7 Å2, given in ref.[10g]].
which appear well-suited to stabilise this arrangement of water
molecules. According to the nomenclature for water clus-
ters[11a–11c] the 1D-tape in the present structure can be as-
signed as T4(2), in which the smallest supramolecular entity is
represented by a cyclic tetramer of water molecules, two of
them shared between adjacent rings (Figure 9b and Figure 9c).
It should be noted that the T4(2) kind of arrangement of
water molecules[11a] occurs rather rarely,[10f,10g] and in environ-
ments based on metal-free organic systems such arrangement
Within the tape structure shown in Figure 9b, the oxygen
atom O2 acts as a single hydrogen-bond acceptor, whereas its
hydrogen atoms are associated with two water molecules. The
water tape is connected to the host framework through
O–H···N hydrogen-bonding [O1–H2O···N1 1.94 Å, 170°], so that
the oxygen O1 acts as a bifurcated acceptor. An excerpt of the
crystal structure showing the mode of hydrogen bonding is
depicted in Figure 9b.
The O···O distances in the tetramer range from 2.830(2) to
has been observed extremely rarely (for an example, see 2.917(2) Å. The average separation of 2.864(2) Å is considerably
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Figure 10. (a) Illustration of the packing diagram of 15·H2O viewed down the crystallographic c-axis. Hydrogen atoms of the host molecules are omitted for
clarity. Hydrogen-bond interactions are marked as dashed lines, π···π arene interactions as broken double lines. (b) Dimer (15·H2O)2 held together by two
water molecules through O–H···N hydrogen-bonding. The following O–H···N interactions (H···N distance) are shown: O–H···N (a = 2.14 Å, b = 2.63 Å, c =
2.34 Å).
[28]
longer than the corresponding separations in ice Ic
(2.75 Å) of the carbaldehyde 4, was found to crystallise in the mono-
and ice Ih (2.759 Å), but deviates slightly from the O···O distance clinic space group C2/c with two independent, but conforma-
of 2.85 Å in liquid water.[29] A view of the packing structure as tionally similar host molecules and 3.5 molecules of water in
shown in Figure 10a reveals that the crystal consists of one- the asymmetric part of the unit cell. In the solid-state structure,
dimensional host–guest aggregates extending parallel to the the host molecules exist in the zwitterionic form, in which the
011 plane. Host–host interactions are restricted to C–H···N acidic proton has migrated to the ring nitrogen atom N1A
hydrogen-bonding and π···π arene stacking forces the latter (N1B). The naphthyridinium/carboxylate moiety of the mol-
showing a Cg···Cg distance of 3.817(1) Å.
ecules deviates to a less extent from planarity, possibly because
of intramolecular N–H···O hydrogen-bonding. As is clear from
the packing excerpt in Figure 11a, the independent host mol-
ecules contribute in different way in molecular association. One
of them (host 1) and two of the water molecules (O4, O7) are
connected to form a rotation symmetric complex of the struc-
ture (host)2·3H2O with the oxygen atom O7 located on the sym-
metry axis. The O···O distances within the bicyclic supramolec-
ular motif of the 2:3 complex range from 2.812(2) to 3.004(2) Å.
The carboxylate groups of the second host molecule (host 2)
and the remaining water molecules (O5, O6) are linked together
through O–H···O hydrogen bonds to form twisted supramolec-
ular strands extending along the b-axis (Figure 11b). The small-
est supramolecular element of these 1D-aggregates, the struc-
Crystal growing of 15 from aqueous methanol yields a
monohydrate of the monoclinic space group P1¯ with the asym-
metric unit containing one molecule of the naphthyridine deriv-
ative and one water molecule. The two piperidine moieties of
the molecule adopt an ideal chair conformation. The crystal
structure is composed of dimers (15·H2O)2 held together by the
water molecules through O–H···N hydrogen-bonding (Fig-
ure 10). Within the 2:2 host–guest complex (Figure 10b), one of
the water hydrogen atoms acts as a bifurcated donor for O–
H···N bonding [d(H···N) 2.34(4), 2.63(3) Å], thus creating a cyclic
2
supramolecular motif of the graph set R4 (8). Connection of the
complex molecules by offset face-to-face arene interactions
[Cg···Cg distance 4.364(1) Å] results in formation of supramolec-
ular chains.
ture of which is illustrated in Figure 11b, is given by an eight-
3
The morpholinyl-substituted 1,8-naphthyridine-2-carboxylic membered ring of the graph set R3 (8). Within this hydrogen-
acid 17, which was obtained as a by-product in the synthesis bonding arrangement the Ohost···Owater distances [2.729(2),
Eur. J. Org. Chem. 2017, 6038–6051
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Figure 11. Packing excerpt of 17·H2O (2:3.5) with labelling of relevant atoms (a) and illustration of the 1D water chain connected with the carboxylate groups
of the host molecules. Nitrogen atoms are displayed as cross-hatched (blue) and oxygen atoms as dotted (red) circles. Hydrogen-bond interactions are marked
as broken lines. In (a) the particular ring systems of intermolecular interactions and (b) the strand of water molecules are specified by colour highlighting. In
(b) only the carboxylate groups of the host molecules are shown for clarity. The following C/N/O–H···O interactions (H···O distance) are shown: N–H···O (a =
1.95 Å, d = 2.08 Å), Caryl–H···O (b = 2.47 Å, g = 2.52 Å, h = 2.51 Å, i = 2.61 Å), Cmorph–H···O (c = 2.47 Å, f = 2.53 Å), O–H···O (e = 1.84 Å, j = 1.86 Å, k = 2.08 Å,
l = 2.07 Å, m = 1.92 Å, n = 1.98 Å, o = 2.15 Å).
2.741(2) Å] are significantly shorter than the O···O distances be- hydes represent valuable starting materials for the construction
tween water molecules [2.828(2), 2.919(2) Å]. The different su- of systems that are useful for supramolecular and medicinal
pramolecular aggregates are assembled by N–H···Omorpholine chemistry.
2
and C–H···Ocarboxylate hydrogen bonds [graph R2 (8)] into a
three-dimensional network.
Single-crystal X-ray diffraction studies allowed detailed pack-
ing analysis of four carbaldehydes (2–4 and 6) and six methyl
derivatives (10–15) and provided valuable information on the
supramolecular motifs in the crystal structures of solvent-free
and solvated naphthyridines. The crystal structures of carbalde-
hydes 2–4 and 6 revealed that only in the case of 2 do the
Conclusion
1,8-Naphthyridinecarbaldehydes 1–8, bearing chlorine, pyrrol-
formyl groups of inversion-related molecules form a cyclic pat-
idinyl, piperidinyl or morpholinyl groups, were prepared by
2
oxidation of their methyl-substituted precursors 9–16. Among tern of C–H···O=C hydrogen bonds of the graph set[16,17] R2 (6)
the target compounds 1–16, eleven compounds, 1–8 and 10– [a relatively rare observed dimer synthon[30] in the case of
12, have not previously been described. The prepared carbalde- carbaldehydes]. In addition, the formyl oxygen atom partici-
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2
silica gel (Merck, 63–100 μm) was used. Analytical TLC was per-
formed on commercial Merck Plates coated with TLC Silica Gel 60
F254. 2-Chloro-7-methyl-1,8-naphthyridine (9)[13] and 2,4-dichloro-
3,7-dimethyl-1,8-naphthyridine (13)[14] were synthesised as de-
scribed previously (see also Scheme 1).
pates in a second supramolecular motif, namely R2 (10), with
an aryl hydrogen atom of a neighbouring molecule acting as a
donor. The latter supramolecular motif could also be observed
in the crystal structure of carbaldehyde 6. In contrast to 2 and
6, the formyl group of 3 and 4 does not participate in the
supramolecular motif of the graph set R2 (10), but the formyl General Procedure for the Preparation of Compounds 10–12
oxygen atom is involved in C–H···O=C hydrogen bonds with the
(1 g, 5.6 mmol) dissolved in toluene (50 mL) and the corresponding
CH unit of the piperidine or morpholine ring of a neighbouring
molecule (for comparison of the hydrogen-bonding motifs
2
and 14: A mixture of 2-chloro-7-methyl-1,8-naphthyridine (9)[13]
amine (2 mL) was heated to reflux for 6 h. After removing the sol-
vent in vacuo, water (50 mL) was added and the aqueous phase
found in the crystal structures of 2–4 and 6, see Figure 4). Be-
was extracted with chloroform (3 × 50 mL). The organic phase was
side the C–H···O hydrogen bonds, the pattern of intermolecular
dried with Na2SO4 and the solvent was removed. Specific details for
each compound are given below.
interactions in the crystal structures of 2–4 and 6 is completed
by C–H···N, C=O···π as well as π···π arene (face-to-face) inter-
7-Methyl-2-(pyrrolidin-1-yl)-1,8-naphthyridine (10): Prepared
from 9 and pyrrolidine (2 mL, 1.73 g, 24 mmol). Recrystallisation
from ethanol/water gave 10 (1.03 g, 4.8 mmol, 86 %); m.p. 195–
actions.
A particular structural feature can be seen in the formation
of interesting water clusters, such as the T4(2) water tape, which
was observed in the hydrate of compound 11 (11·2H2O). Given
the rarity of the occurrence of the T4(2)[11a–11c] connection
mode of water molecules (Figure 9), the crystal structure
11·2H2O provides particularly valuable information on the
structural properties of this type of water cluster trapped in a
neutral supramolecular environment. It should be noted that
the stabilisation of water clusters by metal- and salt-free sys-
tems occurs relatively rarely.
1
196 °C. H NMR (500 MHz, CDCl3): δ = 2.02–2.05 (m, 4 H), 2.68 (s, 3
H), 3.62–3.70 (m, 4 H), 6.68 (d, J = 8.9 Hz, 1 H), 6.97 (d, J = 7.9 Hz,
1 H), 7.75 (d, J = 8.9 Hz, 1 H), 7.76 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 25.4, 47.0, 110.2, 114.3, 117.5, 136.2, 136.9,
156.8, 157.7, 161.7 ppm. IR (KBr): ν = 2990, 2867, 1621, 1604, 1475,
˜
1457 cm–1. C13H15N3 (213.28): calcd. C 73.21, H 7.09, N 19.70; found
C 72.85, H 7.37, N 19.62.
7-Methyl-2-(piperidin-1-yl)-1,8-naphthyridine (11): Prepared
from 9 and piperidine (2 mL, 1.72 g, 20 mmol). Recrystallisation
from water/ethanol gave 11 (1.13 g, 4.9 mmol, 89 %); m.p. 86–88 °C.
1H NMR (500 MHz, CDCl3): δ = 1.65–1.71 (m, 6 H), 2.69 (s, 3 H), 3.81–
Interesting networks of hydrogen bonds under participation
of water molecules can also be observed in the hydrates
15·H2O and 17·H2O (2:3.5; crystal structure of a by-product). 3.83 (m, 4 H), 6.95 (d, J = 9.0 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 7.76
(d, J = 7.9 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
The crystal structure of compound 15 is composed of dimers
CDCl3): δ = 24.8, 25.4, 25.9, 46.1, 109.3, 114.4, 118.0, 135.9, 137.3,
(15·H2O)2 that are held together by the water molecules
156.5, 159.2, 161.9 ppm. IR (KBr): ν = 2987, 2925, 1616, 1599, 1467,
˜
through O–H···N hydrogen bonds (Figure 10), and through the
action of one of the water hydrogen atoms as a bifurcated do-
1434 cm–1. C14H17N3 (227.31): calcd. C 73.98, H 7.54, N 18.49; found
C 73.64, H 7.63, N 18.20.
nor for O–H···N bonding, the creation of a cyclic supramolecular
2
motif of the graph set R4 (8) can be realised. In the case of 7-Methyl-2-(morpholin-4-yl)-1,8-naphthyridine (12): Prepared
from 9 and morpholine (2 mL, 2.01 g, 23 mmol). Recrystallisation
from diisopropyl ether gave 12 (1.17 g, 5.1 mmol, 91 %); m.p. 107–
111 °C. H NMR (500 MHz, CDCl3): δ = 2.71 (s, 3 H), 3.82–3.84 (8 H),
the inclusion structure of 17, the water molecules connected
through O–H···O bonding to carboxylate groups of a zwitter-
ionic host molecule create an eight-membered ring of the
1
6.93 (d, J = 9.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz,
1 H), 7.85 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 25.5, 45.3, 66.8, 108.9, 114.9, 118.8, 136.1, 137.7, 156.1, 159.3,
3
graph set R3 (8) as part of infinite supramolecular strands (Fig-
ure 11a and Figure 11b). On the other hand, three water mol-
ecules form a bicyclic motif of O–H···O bonds with participation
of the carboxylate oxygen atoms of a second host molecule
(Figure 11a). It should be noted that knowledge of the detailed
structural properties of different water clusters is of great re-
search interest to the broad scientific community, particularly
to scientists working in the fields of supramolecular and
biomolecular chemistry, atmospheric and surface chemistry,
materials science and crystal engineering.
162.3 ppm. IR (KBr): ν = 2958, 2850, 1600, 1535, 1450, 1438 cm–1
C13H15N3O (229.28): calcd. C 68.10, H 6.59, N 18.33; found C 67.76,
H 6.51, N 18.05.
.
˜
4-Chloro-3,7-dimethyl-2-(piperidin-1-yl)-1,8-naphthyridine (14):
Prepared from 13[14] (3.00 g, 13.2 mmol) and piperidine (3 mL,
2.61 g, 30.7 mmol). Yield: 2.80 g (10.1 mmol, 77 %); m.p. 95–98 °C.
1H NMR (500 MHz, CDCl3): δ = 1.64–1.66 (m, 2 H), 1.72–1.75 (m, 4
H), 2.47 (s, 3 H), 2.74 (s, 3 H), 3.31–3.33 (m, 4 H), 7.21 (d, J = 8.3 Hz,
1 H), 8.27 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
16.9, 24.5, 25.2, 26.0, 51.1, 116.1, 120.5, 123.5, 133.1, 142.0, 154.0,
Experimental Section
162.0, 164.6 ppm. IR (KBr): ν = 2933, 1592, 1537, 1442, 1421,
˜
1137 cm–1. C15H18ClN3 (275.78): calcd. C 65.33, H 6.58, N 15.24;
found C 65.33, H 6.94, N 15.22.
General Information: Melting points (uncorrected) were measured
with a hot-stage microscope (Reichert Thermovar). IR spectra were
obtained with a Perkin–Elmer FTIR 1600 spectrometer as KBr pellet.
1H and 13C NMR spectra were recorded with a Bruker Avance III-
General Procedure for the Preparation of 15 and 16: 4-Chloro-
3,7-dimethyl-2-(piperidin-1-yl)-1,8-naphthyridine (14) and the corre-
500 MHz spectrometer using Me4Si as internal standard. Elemental sponding amine were tempered at 160 °C in a sealed tube for 21 h.
analyses were performed with an Elementar CHN VarioMicro Cube
analyser. Reagent and solvents of reagent grade were commercially
available (Acros Organics, Sigma Aldrich or TCI Deutschland GmbH)
and used without further purification. For column chromatography,
After cooling to room temperature, the precipitate (piperidinium
salt) was filtered off and a first fraction of the product was precipi-
tated by diethyl ether. Afterwards, dichloromethane was added to
the mother liquor, washed with water, dried with Na2SO4 and the
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solvent was removed under reduced pressure. Specific details for
each compound are given below.
24.8, 25.9, 46.1, 112.8, 113.9, 119.8, 137.3, 137.4, 154.2, 156.9, 159.5,
194.6 ppm. IR (KBr): ν = 2935, 2854, 1706, 1616, 1539, 1461,
˜
1421 cm–1. C14H15N3O (241.29): calcd. C 69.69, H 6.27, N 17.41;
found C 69.43, H 6.61, N 17.06.
3,7-Dimethyl-2,4-di(piperidin-1-yl)-1,8-naphthyridine (15): Pre-
pared from 14 (1.20 g, 4.4 mmol) and piperidine (2.5 mL,
25.6 mmol). Purification by column chromatography (ethyl acetate, 7-(Morpholin-4-yl)-1,8-naphthyridine-2-carbaldehyde (4): Pre-
1
Rf = 0.42) gave 15 (0.60 g, 1.8 mmol, 42 %); m.p. 69–72 °C. H NMR pared from 7-methyl-2-(morpholin-1-yl)-1,8-naphthyridine (12;
(500 MHz, CDCl3): δ = 1.64–1.66 (m, 2 H), 1.70–1.75 (m, 10 H), 2.29
(s, 3 H), 2.69 (s, 3 H), 3.24–3.26 (m, 4 H), 3.28–3.32 (m, 4 H), 7.06 (d,
J = 8.3 Hz, 1 H), 8.17 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 16.9, 24.6, 24.8, 25.1, 26.0, 27.0, 50.7, 52.4, 115.3, 117.4,
0.50 g, 2.2 mmol) and SeO2 (0.24 g, 2.2 mmol). Recrystallization
from ethyl acetate gave 4 (0.29 g, 1.2 mmol, 55 %); m.p. 192–193 °C.
1H NMR (500 MHz, CDCl3): δ = 3.85–3.91 (m, 8 H), 7.14 (d, J = 9.1 Hz,
1 H), 7.83 (d, J = 7.9 Hz, 1 H), 7.97 (d, J = 9.1 Hz, 1 H), 8.10 (dd, J =
7.9, 0.8 Hz, 1 H), 10.25 (d, J = 0.7 Hz, 1 H) ppm. 13C NMR (125 MHz,
118.6, 133.2, 155.4, 156.5, 160.3, 166.1 ppm. IR (KBr): ν = 2931, 2848,
˜
1581, 1540, 1463, 1450 cm–1. C20H28N4 (324.47): calcd. C 74.03, H CDCl3): δ = 45.2, 66.7, 112.3, 114.6, 120.1, 137.6, 137.9, 154.4, 156.4,
8.70, N 17.27; found C 73.99, H 8.68, N 17.17.
159.7, 194.3 ppm. IR (KBr): ν = 2966, 2815, 1700, 1612, 1512, 1440,
˜
1419 cm–1. C13H13N3O2 (243.26): calcd. C 64.19, H 5.39, N 17.27;
found C 64.24, H 5.57, N 17.16.
3,7-Dimethyl-4-(morpholin-4-yl)-2-(piperidin-1-yl)-1,8-naphthyr-
idine (16): Prepared from 14 (1.00 g, 3.6 mmol) and morpholine
(2.5 mL, 38.3 mmol). Purification by column chromatography (ethyl
acetate, Rf = 0.30) gave 16 (0.30 g, 0.9 mmol, 25 %); m.p. 144–
145 °C. 1H NMR (500 MHz, CDCl3): δ = 1.64–1.67 (m, 2 H), 1.70–1.75
(m, 4 H), 2.34 (s, 3 H), 2.70 (s, 3 H), 3.30–3.33 (m, 8 H), 3.90–3.92 (m,
4 H), 7.09 (d, J = 8.2 Hz), 8.20 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 16.7, 24.7, 25.1, 26.0, 50.7, 51.0, 67.9, 114.9,
5,7-Dichloro-6-Methyl-1,8-naphthyridine-2-carbaldehyde (5):
Prepared from 2,4-dichloro-3,7-dimethyl-1,8-naphthyridine (13;
1.00 g, 4.4 mmol) and SeO2 (0.50 g, 4.4 mmol). Yield: 0.31 g
1
(1.3 mmol, 30 %); m.p. 138–143 °C. H NMR (500 MHz, CDCl3): δ =
2.69 (s, 3 H), 8.12 (d, J = 8.5 Hz, 1 H), 8.66 (dd, J = 8.5, 0.8 Hz, 1 H),
10.20 (d, J = 0.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.1,
119.1, 123.2, 132.3, 135.8, 142.7, 153.1, 155.0, 156.6, 192.6 ppm. IR
118.4, 119.0, 132.7, 154.6, 155.5, 160.7, 166.0 ppm. IR (KBr): ν = 2850,
˜
2813, 1600, 1581, 1454, 1448 cm–1. C19H26N4O (326.44): calcd. C
69.91, H 8.03, N 17.16; found C 70.19, H 8.22, N 17.25.
(KBr): ν = 3064, 1707, 1577, 1539, 1133 cm–1. C10H6Cl2N2O (241.08):
˜
calcd. C 49.82, H 2.51, N 11.62; found C 49.90, H 2.60, N 11.44.
General Procedure for the Preparation of Compounds 1–8: A
mixture of the corresponding 1,8-naphthyridine (compounds 9–16),
an equimolar amount of SeO2, three drops of water and 1,4-dioxane
(30 mL) were stirred for 4 h at 50 °C. After filtration of SeO2 through
5-Chloro-6-methyl-7-(piperidin-1-yl)-1,8-naphthyridine-2-carb-
aldehyde (6): Prepared from 4-chloro-3,7-dimethyl-2-(piperidin-1-
yl)-1,8-naphthyridine (14) (0.80 g, 2.9 mmol) and SeO2 (0.31 g,
2.9 mmol). Yield: 0.55 g (1.0 mmol, 65 %); m.p. 131–136 °C. 1H NMR
Celite, the solvent was removed under reduced pressure. The pre- (500 MHz, CDCl3): δ = 1.71–1.73 (m, 2 H), 1.77–1.81 (m, 4 H), 2.53
cipitate was extracted with ethyl acetate, washed with a solution of (s, 3 H), 3.41–3.43 (m, 4 H), 7.95 (d, J = 8.2 Hz, 1 H), 8.54 (dd, J =
NaHCO3 and dried with Na2SO4. After removing the solvent, the
crude product was purified as given below.
8.2, 0.7 Hz, 1 H), 10.29 (d, J = 0.7 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 17.8, 24.4, 25.8, 51.0, 116.0, 120.8, 127.0, 134.7, 142.0,
154.1, 165.2, 193.8 ppm. IR (KBr): ν = 2925, 2838, 1706, 1598, 1538,
˜
7-Chloro-1,8-naphthyridine-2-carbaldehyde (1): Prepared from
2-chloro-7-methyl-1,8-naphthyridine (9; 0.50 g, 2.8 mmol) and SeO2
(0.31 g, 2.8 mmol). Recrystallisation of the crude product from wa-
ter/ethanol gave 1 (0.30 g, 1.6 mmol, 56 %); m.p. 214–215 °C. 1H
NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 8.3 Hz, 1 H), 8.16 (d, J =
8.4 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 8.41 (d, J = 8.2 Hz, 1 H), 10.29
1434, 1130 cm–1. C15H16ClN3O (289.76): calcd. C 62.18, H 5.57, N
14.50; found C 61.93, H 5.76, N 14.55.
3-Methyl-2,4-di(piperidin-1-yl)-1,8-naphthyridine-7-carbalde-
hyde (7): Prepared from 3,7-dimethyl-2,4-di(piperidin-1-yl)-1,8-
naphthyridine (15) (0.65 g, 2.0 mmol) and SeO2 (0.22 g, 2.0 mmol).
1
(s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 118.7, 123.9, 125.9, Yield: 0.61 g (1.8 mmol, 90 %); m.p. 93–103 °C. H NMR (500 MHz,
138.6, 139.2, 155.1, 155.3, 155.7, 193.1 ppm. IR (KBr): ν = 3041, 1712,
CDCl3): δ = 1.58–1.71 (m, 12 H), 2.25 (s, 3 H), 3.18–3.32 (m, 8 H),
7.74 (d, J = 8.2 Hz, 1 H), 8.33 (dd, J = 8.2, 0.8 Hz, 1 H), 10.27 (d, J =
0.8 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.6, 24.5, 24.7, 25.9,
26.9, 50.4, 52.4, 114.3, 120.2, 120.5, 134.3, 153.1, 155.5, 156.2, 166.8,
˜
1594, 1538, 1106 cm–1. C9H5ClN2O (192.60): calcd. C 56.12, H 2.62,
N 14.54; found C 55.93, H 2.88, N 14.78.
7-(Pyrrolidin-1-yl)-1,8-naphthyridine-2-carbaldehyde (2): Pre-
pared from 7-methyl-2-(pyrrolidin-1-yl)-1,8-naphthyridine (10; 0.3 g,
1.4 mmol) and SeO2 (0.15 g, 1.4 mmol). Yield: 0.20 g (0.9 mmol,
194.7 ppm. IR (KBr): ν = 2931, 2846, 1704, 1579, 1540, 1463,
˜
1438 cm–1. C20H26N4O (338.45): calcd. C 70.98, H 7.74, N 16.55;
found C 70.84, H 7.83, N 16.84.
1
63 %); m.p. 151 °C. H NMR (500 MHz, CDCl3): δ = 2.08–2.10 (m, 4
H), 3.50–3.90 (m, 4 H), 6.89 (d, J = 9.0 Hz, 1 H), 7.74 (d, J = 7.9 Hz,
1 H), 7.86 (d, J = 9.0 Hz, 1 H), 8.03 (dd, J = 7.9, 0.8 Hz, 1 H), 10.26
3-Methyl-4-(morpholin-4-yl)-2-(piperidin-1-yl)-1,8-naphthyr-
idine-7-carbaldehyde (8): Prepared from 3,7-dimethyl-4-(morphol-
(d, J = 0.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.5, 47.2, in-4-yl)-2-(piperidin-1-yl)-1,8-naphthyridine (16, 0.19 g, 0.6 mmol)
113.5, 113.9, 119.7, 136.9, 137.5, 154.0, 157.0, 158.0, 194.7 ppm. IR and SeO2 (0.06 g, 0.6 mmol). Yield: 0.11 g 0.3 mmol, 55 %); m.p.
(KBr): ν = 2952, 2865, 1693, 1613, 1535, 1473, 1456 cm–1. C13H13N3O 178–179 °C. 1H NMR (500 MHz, CDCl3): δ = 1.68–1.71 (m, 2 H), 1.74–
˜
(227.27): calcd. C 68.70, H 5.77, N 18.49; found C 68.54, H 5.94, N
18.21.
1.78 (m, 4 H), 2.39 (s, 3 H), 3.35–3.42 (m, 6 H), 3.93–3.95 (m, 4 H),
7.85 (d, J = 8.3 Hz, 1 H), 8.46 (dd, J = 8.3, 0.7 Hz, 1 H), 10.27 (d, J =
0.7 Hz, 1 H, CHO) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.5, 24.6,
25.9, 50.5, 51.0, 67.8, 114.6, 120.1, 121.2, 134.0, 153.4, 154.4, 155.5,
166.7, 194.5 ppm. C19H24N4O2 (340.42): calcd. C 67.04, H 7.11, N
16.46; found C 66.81, H 7.49, N 16.26.
7-(Piperidin-1-yl)-1,8-naphthyridine-2-carbaldehyde (3): Pre-
pared from 7-methyl-2-(piperidin-1-yl)-1,8-naphthyridine (11;
0.80 g, 3.5 mmol) and SeO2 (0.39 g, 3.5 mmol). Purification by col-
umn chromatography (ethyl acetate, Rf = 0.68) gave 3 (0.60 g,
2.4 mmol, 71 %); m.p. 102–105 °C. 1H NMR (500 MHz, CDCl3): δ =
X-ray Crystal Structure Determination: Crystals of the com-
1.68–1.75 (m, 6 H), 3.87–3.89 (m, 4 H), 7.15 (d, J = 9.1 Hz, 1 H), 7.76 pounds studied were grown by slow evaporation of the solvent
(d, J = 7.9 Hz, 1 H), 7.88 (d, J = 9.1 Hz, 1 H), 8.03 (dd, J = 7.9, 0.8 Hz,
(solvent mixtures) at room temperature. Crystals suitable for X-ray
diffraction experiments were selected under a microscope and
1 H), 10.25 (d, J = 0.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
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7, 5270–5276; e) J.-M. Fang, S. Selvi, J.-H. Liao, Z. Slanina, Ch. T. Chen, P.-
T. Chou, J. Am. Chem. Soc. 2004, 126, 3559–3566.
mounted on a glass fibre. Crystal data of 2, 6, 10–12, 14 and 17
were collected with a Bruker X8 APEX CCD diffractometer using ꢀ
and ω scans. Absorption corrections were applied using the SAD-
ABS program (6, 13, 14).[31] Crystal data of 3, 4, 13 and 15 were
collected with a STOE IPDS 2T image plate diffractometer. Absorp-
tion correction was applied using the STOE X-Shape program.[32]
Preliminary structure models were derived by application of direct
methods (4, 11, 15, 17) and using SIR2014 (2, 3, 6, 10)[34] and were
refined by full-matrix least-squares calculation based on F2 for all
reflections.[33] All non-hydrogen atoms were refined anisotropically.
With the exception of the water hydrogen atoms in 11·2H2O and
15·H2O and the hydrogen atoms H1N and H4N in 17·H2O (2:3.5),
all other hydrogen atoms were included in the models in calculated
positions and were refined as constrained to bonding atoms.
[5]
a) S. V. Kolotuchin, S. C. Zimmerman, J. Am. Chem. Soc. 1998, 120, 9092–
9093; b) C.-Y. Huang, L. A. Cabell, E. V. Anslyn, J. Am. Chem. Soc. 1994,
116, 2778–2792; c) S. Goswami, S. Dey, J. F. Gallagher, A. J. Lough, S.
García-Granda, L. Torre-Fernández, I. Alkorta, J. Elguero, J. Mol. Struct.
2007, 846, 97–107; d) C. Alvarez-Rua, S. García-Granda, S. Goswami, R.
Mukherjee, S. Dey, R. M. Claramunt, M. D. Santa María, I. Rozas, N. Jagero-
vic, I. Alkortae, J. Elguero, New J. Chem. 2004, 28, 700–707; e) M. F. Mayer,
S. Nakashima, S. C. Zimmermann, Org. Lett. 2005, 7, 3005–3008; f) A.
Fernández-Mato, M. Sanchez-Andújar, B. Pato-Doldán, M. A. Señarís-Rod-
ríguez, C. Platas-Iglesias, D. Tordera, H. J. Bolink, J. M. Quintela, C. Pein-
ador, M. D. García, Cryst. Growth Des. 2014, 14, 3849–3856; g) Y. Ferrand,
A. M. Kendhale, J. Carric, B. Kauffmann, I. Huc, Angew. Chem. Int. Ed.
2010, 49, 1778–1781; Angew. Chem. 2010, 122, 1822; h) S. K. Seth, N. K.
Das, K. Aich, D. Sen, H.-K. Fun, S. Goswami, J. Mol. Struct. 2013, 1048,
157–165.
a) K. Ghosh, T. Sen, R. Fröhlich, J. Inclusion Phenom. Macrocyclic Chem.
2010, 68, 193–199; b) A. J. Bailey, P. N. Horton, M. C. Grossel, CrystEng-
Comm 2010, 12, 4074–4079; c) M. A. Farrán, D. S. María, M. A. García,
R. M. Claramunt, G. J. Clarkson, J. Inclusion Phenom. Macrocyclic Chem.
2015, 81, 57–69; d) Z. Li, W. Zhao, X. Li, Y. Zhu, L. Wei, M. Tang, H. Zhang,
Inorg. Chem. 2012, 51, 12444–12449; e) D.-H. Wang, Y. Zhang, Z. Gong,
R. Sun, D.-Z. Zhao, C.-L. Sun, RSC Adv. 2015, 5, 50540–50543; f) C.-Y.
Huang, K.-Y. Kuan, Y.-H. Liu, S.-M. Peng, S.-T. Liu, Organometallics 2014,
33, 2831–2836; g) Y. L. Duan, Y. G. Shi, J. H. Chen, X. H. Wu, G. K. Wang,
Y. Zhou, Tetrahedron Lett. 2012, 53, 6544–6547.
CCDC 1531035 (for 2), 1531024 (for 3), 1531029 (for 4), 1531033
(for 6), 1531025 (for 10), 1531026 (for 11), 1531034 (for 12),
1531027 (for 13), 1531028 (for 14), 1531030 (for 15), and 1531031
(for 17) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[6]
Supporting Information (see footnote on the first page of this
article): Crystallographic data (Tables S1–S6, Figures S1–S3). Copies
1
of the H and 13C NMR spectra of 1–8 and 10–12 (Figures S4–S25).
[7]
For examples of studies using heterocyclic aldehydes as starting materi-
als in the synthesis of artificial receptors, see: a) J.-R. Rosien, W. Seichter,
M. Mazik, Org. Biomol. Chem. 2013, 11, 6569–6579; b) N. Koch, J.-R. Ro-
sien, M. Mazik, Tetrahedron 2014, 70, 8758–8767; c) M. Mazik, J. Lippe, J.
Org. Chem. 2013, 78, 9013–9020; d) J. Lippe, M. Mazik, J. Org. Chem.
2015, 80, 1427–1439; e) M. Mazik, A. Hartmann, Beilstein J. Org. Chem.
2010, 6, No 9; f) C. Sonnenberg, A. Hartmann, M. Mazik, Nat. Prod. Com-
mun. 2012, 7, 321–326; g) M. Mazik, C. Geffert, Org. Biomol. Chem. 2011,
9, 2319–2326; h) M. Mazik, M. Kuschel, Chem. Eur. J. 2008, 14, 2405–
2419; i) F. Amrhein, J. Lippe, M. Mazik, Org. Biomol. Chem. 2016, 14,
10648–10659; j) N. Koch, M. Mazik, Synthesis 2016, 48, 2757–2767.
Selected examples showing the usefulness of heterocyclic aldehydes in
the preparation of building blocks for self-assembled aggregates, see: a)
M. Mazik, D. Bläser, R. Boese, J. Org. Chem. 2005, 70, 9115–9122; b) M.
Mazik, D. Bläser, R. Boese, Tetrahedron 2001, 57, 5791–5797; c) M. Mazik,
D. Bläser, R. Boese, Chem. Eur. J. 2000, 6, 2865–2873; d) M. Mazik, D.
Bläser, R. Boese, Tetrahedron 1999, 55, 7835–7840; e) M. Mazik, D. Bläser,
R. Boese, Tetrahedron Lett. 1999, 40, 4783–4786.
Acknowledgments
Financial support of the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
Keywords: Hydrogen bonds · Synthons · Hydrates · Water
cluster · Solvates · Supramolecular structures
[8]
[1] For examples of reviews, see: a) V. P. Litvinov, Russ. Chem. Rev. 2004, 73,
637–669; b) J. K. Bera, N. Sadhukhan, M. Majumdar, Eur. J. Inorg. Chem.
2009, 4023–4038; c) Y. Sato, S. Nishizawa, K. Yoshimoto, T. Seino, T. Ichi-
hashi, K. Morita, N. Teramae, Nucleic Acids Res. 2009, 37, 1411–1422.
[2] a) D. J. Brown, J. A. Ellman, E. C. Taylor, The Chemistry of Heterocyclic
Compounds, The Naphthyridines; John Wiley, 2008; b) A. R. Katritzky, Ad-
vances in Heterocyclic Chemistry, 2006, Vol. 91.
[9]
a) R. Ludwig, Angew. Chem. Int. Ed. 2001, 40, 1808–1827; Angew. Chem.
2001, 113, 1856; b) T. Köddermann, F. Schulte, M. Huelsekopf, R. Ludwig,
Angew. Chem. Int. Ed. 2003, 42, 4904–4908; Angew. Chem. 2003, 115,
5052.
[3] For selected examples, see: a) M. Mazik, Preparation of aminonaphthyr-
idine derivatives as antiinfective agents. PCT Int. Appl. 2008113558, 2008;
b) M. Mazik, Preparation of Poly(hetero)arenes as Antiinfective Agents, PCT
Int. Appl. 2008113557, 2008; c) P. L. Ferrarini, C. Mori, V. Calderone, L.
Calzolari, P. Nieri, G. Saccomanni, E. Martinotti, Eur. J. Med. Chem. 1999,
34, 505–513; d) G. Y. Lesher, E. J. Froelich, M. D. Gruett, J. H. Bailey, R. P.
Brundage, J. Med. Chem. 1962, 5, 1063–1065; e) A. Madaan, R. Verma, V.
Kumar, A. T. Singh, S. K. Jain, M. Jaggi, Arch. Pharm. Chem. Life Sci. 2015,
348, 837–860; f) M. Manera, M. G. Cascio, V. Benetti, M. Allará, T. Tuccin-
ardi, A. Martinelli, G. Saccomanni, E. Vivoli, C. Ghelardini, V. Di Marzo, P. J.
Ferrarini, Bioorg. Med. Chem. Lett. 2007, 17, 6505–6510; g) P. L. Ferrarini,
C. Mori, M. Badawneh, V. Calderone, L. Calzolari, T. Loffredo, E. Martinotti,
G. Saccomanni, Eur. J. Med. Chem. 1998, 33, 383–397; h) V. Kumar, M.
Jaggi, A. T. Singh, A. Madaan, V. Sanna, P. Singh, P. K. Sharma, R. Irchhaiya,
A. C. Burman, Eur. J. Med. Chem. 2009, 44, 3356–3362; i) A. Madaan, V.
Kumar, R. Verma, A. T. Singh, S. K. Jain, M. Jaggi, Int. Immunopharmacol.
2013, 15, 606–613; j) P. M. Sivakumar, G. Iyer, M. Doble, Med. Chem. Res.
2012, 21, 788–795.
[10]
For examples of studies on water cluster, see: a) S. Vaitheeswaran, H. Yin,
J. C. Rasaiah, G. Hummer, Proc. Natl. Acad. Sci. USA 2004, 101, 17002–
17005 (theoretical calculations) b) F. N. Keutsch, R. J. Saykally, Proc. Natl.
Acad. Sci. USA 2001, 98, 10533–10540 (experimentally studies in the gas
phase) c) L. J. Barbour, G. W. Orr, J. L. Atwood, Nature 1998, 393, 671–
673 (solid state studies) d) S. O. Kang, D. Powell, V. W. Day, K. Bowman-
James, Cryst. Growth Des. 2007, 7, 606–608 (solid state) e) K. Dąbrowa,
M. Ceborska, J. Jurczak, Cryst. Growth Des. 2014, 14, 4906–4910 (solid
state) f) Y.-T. Wang, G.-M. Tang, Z.-M. Liu, X.-H. Yi, Cryst. Growth Des. 2007,
7, 2272–2275 [example of T4(2) water tape in the crystalline state, metal-
free system]; g) A. Paul, R. K. Gupta, M. Dubey, S. Gunjan, B. Koch, G.
Hundal, M. S. Hundal, D. S. Pandey, RSC Adv. 2014, 4, 41228–41236 [ex-
ample of T4(2) water tape in the crystalline state, metal-containing sys-
tem]; h) G. E. Kostakis, G. Abbas, C. E. Anson, A. K. Powell, CrystEngComm
2009, 11, 82–86 [example of T4(2)6(2) water tape, metal-containing sys-
tem]; i) X. Zhu, Y.-F. Feng, M. Li, B.-L. Li, Y. Zhang, CrystEngComm 2012,
14, 79–82.
[4] For examples of artificial receptors bearing naphthyridine units: a) M.
Mazik, H. Cavga, Eur. J. Org. Chem. 2007, 3633–3638; b) M. Mazik, W.
Sicking, Chem. Eur. J. 2001, 7, 664–670; c) J. Cuntze, L. Owens, V. Alcázar,
P. Seiler, F. Diederich, Helv. Chim. Acta 1995, 78, 367–390; d) S.-I. Tamaru,
M. Yamamoto, S. Shinkai, A. B. Khasanow, T. W. Bell, Chem. Eur. J. 2001,
[11]
For classification of a number of common aggregation states adopted
by hydrogen-bonded water molecules in organic solid-state structures,
see: a) L. Infantes, S. Motherwell, CrystEngComm 2002, 4, 454–461; b) L.
Infantes, J. Chisholm, S. Motherwell, CrystEngComm 2003, 5, 480–486; c)
Eur. J. Org. Chem. 2017, 6038–6051
www.eurjoc.org
6050
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
M. Mascal, L. Infantes, J. Chisholm, Angew. Chem. Int. Ed. 2006, 45, 32–
36; Angew. Chem. 2006, 118, 36. For an earlier description of hydrates,
see: d) G. R. Desiraju, J. Chem. Soc., Chem. Commun. 1991, 426–428.
[12] a) For a discussion on the role of water in the stabilisation of supramo-
lecular complexes and biological systems, see: F. Biedermann, W. M. Nau,
H.-J. Schneider, Angew. Chem. Int. Ed. 2014, 53, 11158–11171; Angew.
Chem. 2014, 126, 11338; b) For unique complexation of H3O+HO– by the
hydroxy groups of an organic molecule, which are able to assume the
role of water molecules in the hydrated hydronium and hydroxide ion
complexes, see: M. Stapf, W. Seichter, M. Mazik, Chem. Eur. J. 2015, 21,
6350–6354.
[23] a) M. Nishio, Y. Umezawa, K. Honda, S. Tsuboyama, H. Suezawa, CrystEng-
Comm 2009, 11, 1757–1788; b) M. Nishio, Y. Umezawa, H. Suezawa, S.
Tsuboyama, in The Importance of Pi-Interactions in Crystal Engineering,
Frontiers in Crystal Engineering (Eds.: E. R. T. Tiekink, J. Zukerman-Schpec-
tor), Wiley, Chichester, 2012, pp. 1–39.
[24] A. Mukherjee, S. Tothadi, G. R. Desiraju, Acc. Chem. Res. 2014, 47, 2514–
2524.
[25] P. Metrangolo, G. Resnati, T. Pilati, S. Biella, Halogen Bonding, Structure
and Bonding (Eds.: P. Metrangolo, G. Resnati), Springer-Verlag, Berlin, Hei-
delberg, 2008, Vol. 126, pp. 101–136.
[26] Y. N. Imai, Y. Inoue, I. Nakamishi, K. Kitaura, Protein Sci. 2008, 17, 1129–
1137.
[13] E. V. Brown, J. Org. Chem. 1965, 30, 1607–1610.
[27] For examples of discussions on solvates, see: a) A. Nangia, G. R. Desiraju,
Chem. Commun. 1999, 605–606; b) C. H. Görbitz, H.-P. Hersleth, Acta
Crystallogr., Sect. B 2000, 56, 526–534; c) T. L. Threlfall, Analyst 1995, 120,
2435–2460; d) U. J. Griesser, The importance of solvates, in Polymorphism:
in the Pharmaceutical Industry (Ed.: R. Hilfiker), Wiley-VCH, Weinheim, Ger-
many, 2006, pp. 2711–230.
[14] M. Badawneh, C. Manera, C. Mori, G. Saccomanni, P. L. Ferrarini, Farmaco
2002, 57, 631–639.
[15] S. Goswami, R. Mukherjee, R. Mukherjee, S. Jana, A. C. Maity, A. K. Adak,
Molecules 2005, 10, 929–936.
[16] a) J. Grell, J. Bernstein, G. Tinhofer, Acta Crystallogr, B: Struct. Sci. 2000,
56, 166 (Erratum), Acta Crystallogr., Sect. B 1999, 55, 1030–1043; b) M. C.
Etter, J. C. MacDonald, J. Bernstein, Acta Crystallogr., Sect. B 1990, 46,
256–262; c) M. C. Etter, J. Phys. Chem. 1991, 95, 4601–4610.
[17] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem. Int. Ed.
Engl. 1995, 34, 1555–1573; Angew. Chem. 1995, 107, 1689.
[18] A. J. Bondi, Phys. Chem. 1964, 68, 441–451.
[19] G. R. Desiraju, T. Steiner, The Weak Hydrogen Bond in Structural Chemistry
and Biology Oxford University Press, New York, 1999.
[20] L. M. Salonen, M. Ellermann, F. Diederich, Angew. Chem. Int. Ed. 2011, 50,
4808–4842; Angew. Chem. 2011, 123, 4908.
[21] C. R. Martinez, B. L. Iverson, Chem. Sci. 2012, 3, 2191–2201.
[22] X. L. Gao, L. P. Lu, M. L. Zhu, Acta Crystallogr., Sect. C: Cryst. Struct. Com-
mun. 2009, 65, o123–125.
[28] H. König, Z. Kristallogr. 1943, 105, 279–286.
[29] A. H. Narten, W. E. Thiessen, L. Blum, Science 1982, 217, 1033.
[30] For a discussion on supramolecular synthons, see: G. R. Desiraju, Angew.
Chem. Int. Ed. Engl. 1995, 34, 2311–2327; Angew. Chem. 1995, 107, 2541.
[31] SADABS, Bruker AXS Inc., Madison, Wisconsin, USA, 2010.
[32] X-SHAPE, STOE&Cie GmbH, Darmstadt, Germany.
[33] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112–122.
[34] SIR2014: M. C. Burla, R. Caliandro, B. Carrozzini, G. L. Cascarano, C. Giaco-
vazzo, M. Mallamo, A. Mazzone, G. Polidori, J. Appl. Crystallogr. 2015, 48,
306–309.
Received: August 24, 2017
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