Regioselective Synthesis of V-Shaped Bistriazinyl-phenanthrolines

Article abstract of DOI:10.1021/acs.joc.5b01380

A new, regioselective synthesis of V-shaped 2,9-bis(6-(4-halophenyl)-1,2,4-triazin-3-yl)-1,10-phenanthrolines (4XPhBTPhen) ligands was developed, creating access to a simple and reliable synthesis of precursors for future supramolecular actinide complexing systems. Described is a reactant-directed regioselective synthetic method, which was found to be high yielding and reliable and yields exclusively 6,6′-phenyl BTPhen derivatives (including 4-chloro and 4-bromo) in five simple steps. Molecular and crystal structures of PhBTP and PhBTPhen products are fully determined and both were found to be in space group C2/c. Additionally, molecular and crystal structures of Z and E isomers of 2-hydrazono-2-phenylacetaldehyde oxime, a reagent in the synthetic route, reveal existence of strong intramolecular N-H?O hydrogen bonding in the Z isomer explaining its lower solubility in water.

Full text of DOI:10.1021/acs.joc.5b01380

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Regioselective synthesis of Vꢀshaped
bistriazinylꢀphenanthrolines
Niall T. Coogan†, Michael A. Chimes†, James Raftery, Pavle Mocilac* and Melissa A. Denecke
School of Chemistry, University of Manchester, Oxford Road, M139PL, United Kingdom
* Corresponding author: Tel. +441612754296, Fax., E-mail: pavle.mocilac@manchester.ac.uk.
†Authors contributed equally.
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ABSTRACT: A new, regioselective synthesis of Vꢀshaped 2,9ꢀbis(6ꢀ(4ꢀhalophenyl)ꢀ1,2,4ꢀ
triazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthrolines (4XPhBTPhen) ligands was developed, creating access to a
simple and reliable synthesis of precursors for future supramolecular actinide complexing
systems. Described is a reactantꢀdirected regioselective synthetic method, which was found to be
high yielding, reliable, and yields exclusively 6,6’ꢀphenyl BTPhen derivatives (including 4ꢀ
chloro and 4ꢀbromo) in five simple steps. Molecular and crystal structures of PhBTP and
PhBTPhen products are fully determined and both were found to be in space group C2/c.
Additionally, molecular and crystal structures of Z and E isomers of 2ꢀhydrazonoꢀ2ꢀ
phenylacetaldehyde oxime, a reagent in the synthetic route, reveal existence of strong
intramolecular N—H···O hydrogen bonding in the Z isomer explaining its lower solubility in
water.
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INTRODUCTION
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In the last two decades bistriazinylꢀbipyridines (BTBP, Figure 1a)1 and bistriazinylꢀ
phenantrolines (BTPhen, Figure 1b)2 have been developed as highly selective extractands for
separation of actinides (An) and lanthanides (Ln) as part of the partition and transmutation
strategy (P&T) for nuclear waste management.3ꢀ5 Tetradentate BTBP ligands (Figure 1a) were
proven to be superior to previously developed tridentate bistriaziylꢀpiridines (BTP)6 especially in
terms of stability to hydrolysis and radiolysis.7ꢀ9 The CyMe4ꢀBTBP10 ligand is now considered to
be a standard reference ligand for development of An/Ln nuclear separation processes. The
advent of BTPhen ligands2,11ꢀ13 improved the kinetics of complexation and CyMe4ꢀ
BTPhen2,11,12,14,15 is today a promising alternative to CyMe4ꢀBTBP.
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Figure 1: a) BTBP b) BTPhen c) PhBTPhen (X = H) and 4XPhBTPhen (X = Br, Cl)
BTPhen ligands complex An(III)/Ln(III) cations in a 2:1 ratio; two BTPhen molecules
donate eight nitrogen atoms to bind one cation. Ideally the two ligand molecules would be
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oriented relative to each other by a 90° angle.11 In reality, however, the angle formed between
the two ligands is less than 90° as a water or nitrate molecule is also found in the central metal
ion primary coordination sphere, yielding a metal cation coordination number of 9 or 10.2,11
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One can conceive a hypothetical ligand incorporating two BTPhen moieties, held in
proximity to each other at a 90° orientation and at approximately the ideal distance for
complexation. Such a ligand should have the ability to complex An(III)/Ln(III) cations in a 1:1
ratio and may be thermodynamically superior16 to current ligands forming 2:1 or 3:1 complexes.
Ideally such a ligand should be flexible enough that complexes can form quickly and easily and
be able to sterically accommodate additional nitrate or water molecules, as well as be easily
stripped in a separation process application. A straightforward candidate system comprises two
mechanically interlocked macrocycles, each containing a BTPhen moiety, forming a
supramolecular catenane.17 The catenanes are well known and widely investigated molecules in
the area of supramolecular and macrocyclic chemistry and have been shown to have unique
complexing behaviour.18 We are developing BTPhen based catenanes, designed to have high
affinity for fꢀblock elements. Some current trends in supramolecular chemistry are already
directed towards utilisation of fꢀelements.19
The first step towards a BTPhenꢀbased catenane is formation of appropriate precursor
molecules. Phenanthroline based catenanes18 are topologically similar to BTPhen moieties,
therefore an extended Vꢀshaped BTPhen molecule capable of undergoing macrocyclisation
reaction to the desired catenane is a promising precursor. We have targeted synthesizing such a
Vꢀshaped BTPhen precursor, where additional 4ꢀbromophenyl rings are added onto the BTPhen
1,2,4ꢀtriazine rings at their 6 and 6’ positions (2,9ꢀbis(6ꢀ(4ꢀbromophenyl)ꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ
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1,10ꢀphenanthroline, 4BrPhBTPhen, Figure 1c). A chloro version (4ClPhBTPhen Figure 1c)
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with chlorine atoms instead of bromine is also interesting for macrocyclisation.
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Current synthetic strategy for BTPhens is condensation of phenanthroline
biscarbohydrozonamide with symmetric alkyl or phenyl diketones to yield various disubstituted
BTPhens.2,11ꢀ15,20 An analogous synthetic pathway to 4BrPhBTPhen would be reaction of
phenanthroline biscarbohydrozonamide with an asymmetric dione, such as 2ꢀ(4ꢀbromophenyl)ꢀ
glyoxal. However, due to the better reactivity of aldehyde with the hydrazine moiety formation
of the undesired product, 5ꢀsubstituted 1,2,4ꢀtriazine ring, will be favoured. Since two triazine
rings have to be formed the expected yield of the 6,6’ꢀsubstituted Vꢀshaped BTPhen would be
unacceptably low. Therefore, a different synthetic strategy is needed to synthesise 4XPhBTPhen
ligands (X = Br, Cl); herein we report successful development of a new regiospecific synthetic
route for their synthesis.
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Possible new strategies
Several strategies for regioselective synthesis of 6,6’ꢀsubstituted BTPhens were considered based
on literature sources21ꢀ25 describing formation of 3,6ꢀdisubstituted 1,2,4ꢀtriazine rings. The first
(route A) involves deprotonation of 1,10ꢀphenanthrolineꢀ2,9ꢀdicarboxamide with sodium tertꢀ
butoxide, condensation of the deprotonated dicarboxamide with 2ꢀ(4ꢀbromophenyl)ꢀglyoxal to
form
(N2Z,N9Z)ꢀN2,N9ꢀbis(2ꢀ(4ꢀbromophenyl)ꢀ2ꢀoxoethylidene)ꢀ1,10ꢀphenanthrolineꢀ2,9ꢀ
dicarboxamide and final formation of the triazine rings by treating the product with hydrazine.21
The second strategy (route B) starts with conversion of 1,10ꢀphenanthrolineꢀ2,9ꢀdicarbaldehyde
into 2,9ꢀbis((E)ꢀhydrazonomethyl)ꢀ1,10ꢀphenanthroline and subsequent condensation of the
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obtained bishydrazone with (Z)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀoxoacetaldehyde oxime into the desired
4BrPhBTPhen ligand.22 The third strategy (route C) is a modification of route B: instead of
reacting 1,10ꢀphenanthrolineꢀ2,9ꢀdicarbaldehyde with hydrazine, (Z)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀ
oxoacetaldehyde oxime is allowed to react with hydrazine to form (1E,2Z)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀ
hydrazonoacetaldehyde oxime; subsequent condensation with 1,10ꢀphenanthrolineꢀ2,9ꢀ
dicarbaldehyde yields the desired 4BrPhBTPhen ligand product.23ꢀ25
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RESULTS AND DISCUSION
Investigation of new synthetic strategies: model reactions
Since the key reagent, 2,9ꢀdimethylꢀ1,10ꢀphenanthroline or neocuproine is commercially
available but relatively expensive all strategies were initially tested using pyridine (Scheme 1)
instead of phenanthroline derivatives, yielding the corresponding 2,6ꢀbis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ
3ꢀyl)pyridine (6,6’ꢀPhBTP) derivative. In addition, the nonꢀsubstituted version of the precursor
was first synthesised giving the phenyl derivatives.
Route A: Synthesis of the starting reagents for route A in Scheme 1, pyridineꢀ2,6ꢀ
dicarboxamide (
was obtained from a cascade of simple reactions26 as a pure product in
was synthesised27 successfully but was found to be in
1) and 2ꢀphenylglyoxal (2), are described experimental section.
Compound
1
excellent yield (83%). Compound
2
the form of a hydrate, which could not be fully dried. Further challenges for this synthetic
route A were the insolubility of compound in most organic solvents (only sparingly
1
soluble in THF) and failed attempts of deprotonation with sodium tertꢀbutoxide. As route
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A was also not expected to be regioselective (some 5,5’ and 5,6 products were expected),
this route A was abandoned.
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Route A
Route B
O
Route C
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SeO2
O
O
HO
OH
O
O
N
N
N
1,4-dioxane
3 (75%)
1(83%)
NH2
NH2
O
H2N-NH2/EtOH
1. t-BuONa/THF
2.
SeO2
1. EtONa/EtOH
2. Amyl-ONO
3. AcOH
N
N
O
H2N
N
NH2
2
NH2
4 (76%)
O
x
O
N
x
N
N
OH
OH
H2N-NH2
O
O
5 (30%)
6 (52%)
O
N
O
N
N
EtOH/RT
N
N
N
N
AcOH/90°C/65 min
N
N
N
N
N
N
H2N-NH2
N
N
N
N
OH HO
8 (45%)
7 (90%)
Scheme 1: Possible synthetic strategies to obtain 2,6ꢀbis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)pyridine (compound
8, 6,6’ꢀPhBTP),
Route B Oxidation28 of pyridineꢀ2,6ꢀdiyldimethanol with selenium dioxide gave pyridineꢀ
2,6ꢀdicarbaldehyde (
3
) in 75% yield. Compound
3
was reacted29 with hydrazine
)ꢀ
monohydrate in ethanol at room temperature overnight and gave 2,6ꢀbis((
E
hydrazonomethyl)pyridine (
4
) in good yield (76%). (
E)ꢀ2ꢀoxoꢀ2ꢀphenylacetaldehyde
oxime or isoꢀnitrosoacetophenone (
5
) was made23ꢀ25,30,31 by deprotonation of
acetophenone with sodium ethoxide, subsequent reaction with isoꢀpenthyl nitrite to yield
sodium oximate and neutralisation by addition of acetic acid;
5 was obtained in a yield of
only 30%. Condensation of compounds
4 and 5
in ethanol, as described in the literature22
was not possible since compound
4 is insoluble in ethanol and other solvents, such as
THF, 1,4ꢀdioxane and acetic acid. Attempts to drive the reaction at higher temperature
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under reflux did not work. Route B was hence necessarily modified to obtain the Vꢀ
precursor products.
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Route C Modification of route B using the synthetic procedures published by
Kozhevnikov23 et al. was chosen for the successful synthesis of 6,6’ꢀphenyl derivatives of
the triazine rings. Treating compound 523,24 with hydrazine monohydrate in ethanol,
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addition of water and cooling of the reaction mixture prompted precipitation of (1
hydrazonoꢀ2ꢀphenylacetaldehyde oxime or isoꢀnitrosoacetophenone hydrazine (
52% yield. Note that the desired ꢀ6 isomer is obtained, as it is significantly less soluble
in water than its ꢀ6 isomer, (1 ,2 )ꢀ2ꢀhydrazonoꢀ2ꢀphenylacetaldehyde oxime. Reaction
of with dicarbaldehyde in ethanol resulted in formation of a yellow, insoluble
precipitate (90% yield), the intermediate 2,6ꢀbis(3ꢀphenylꢀ1ꢀhydroxyꢀ1,4,5ꢀ
triazahexatrieneꢀ6ꢀyl)pyridine ( ), which was then successfully aromatised by heating in
acetic acid at 90°C for 65 minutes to give 2,6ꢀbis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)pyridine or
PhBTP ( ) in acceptable yield (45%). Purification was accomplished by recrystallization
E,2
Z
)ꢀ2ꢀ
6
) with
Z
E
E E
Zꢀ
6
3
7
8
from DMSO.
All characterisation data (NMR, MS and elemental analysis) confirmed the identity
and demonstrated the purity of the product
8. Mass spectroscopy (MALDI) gave a clean
spectrum suggesting absence of eventual ꢀoxide byꢀproduct.
N
The success of route C for the BTP derivative led us to use it for synthesis of 6,6ꢀphenylꢀ
bistriazinylꢀphenanthrolines.
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NH2
O
O
N
N
N
OH
OH
1.EtONa/EtOH
2. iso-amyl-ONO
3. AcOH/H2O
H2N-NH2
X = Br = 12 (48%)
X = Cl = 16 (54%)
EtOH, RT, 30 h
X
X
X = Br = 13 (51%)
X = Cl = 17 (46%)
X
X = H, Br, Cl
NH2
N
N
10
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OH
SeO2, 1,4-dioxane/H2O
reflux, 30 min.
X = H, Br, Cl
Dichloromethane/RT/36h
N
N
X
N
N
O
O
9 (85%)
N
N
N
N
N
N
N
N
AcOH/90°C/65 min
N
N
OH HO
N
N
N
N
N
N
X= H = 11 (63%)
X = Br = 15 (88%)
X = Cl = 19 (63%)
X= H = 10 (77%)
X = Br = 14 (91%)
X = Cl = 18 (51%)
X
X
X
X
Scheme 2: Syntheses of PhBTPhen (11), 4BrPhBTPhen (15) and 4ClPhBTPhen (19
)
Synthesis of 2,9ꢀbis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthroline (PhBTPhen, 11)
The synthesis of PhBTPhen (11, Scheme 2) was performed in an analogous manner but
beginning with oxidation12 of 2,9ꢀdimethylꢀ1,10ꢀphenanthroline (neocuproine) with
selenium dioxide instead of pyridineꢀ2,6ꢀdiyldimethanol. Pure product, 1,10ꢀ
phenanthrolineꢀ2,9ꢀdicarbaldehyde (
9
), was obtained after column chromatography in
was then reacted with ꢀ6 in dichloromethane
) to form the intermediate 2,6ꢀbis(3ꢀ
phenylꢀ1ꢀhydroxyꢀ1,4,5ꢀtriazahexatrieneꢀ6ꢀyl)ꢀ1,10ꢀphenanthroline 10 as yellow,
good yield (85%). Dicarbaldehyde
9
Z
(instead of ethanol, due to better solubility of
9
(
)
insoluble precipitate in good yield (77%). Intermediate 10 was then aromatized by heating
it in acetic acid, giving 2,9ꢀbis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthroline (11) in
63% yield as a yellow powder.
Characterisation data (1HꢀNMR, CꢀNMR, IR, MSꢀMALDI and elemental analysis)
13
1
13
gave sufficient proof that isolated material is compound 11. Both Hꢀ and C NMR
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spectra show no significant presence of impurities or byꢀproducts. A sample suitable for
elemental analysis was obtained by recrystallization from DMSO, the result suggests the
presence of water and DMSO; we assume water and solvent are bound in the inner,
hydrogenꢀaccepting (complexation) cleft of the compound.
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Synthesis
(4XPhBTPhen, X = Br, Cl)
Synthesis of 4XPhBTPhen where X = Br, Cl (15, 19) was performed in a similar manner
as for 11, following the synthetic route C (Scheme 2). However, the halo derivative of
)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀoxoacetaldehyde oxime (12) and ( )ꢀ2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ
of
2,9ꢀbis(6ꢀ(4ꢀhalophenyl)ꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthrolines
5,
(
E
E
oxoacetaldehyde oxime (16) were used. Compounds 12 and 16 were synthesised from
commercially available 4ꢀbromoacetophenone and 4ꢀchloroacetophenone using the same
procedure as for compound
to obtain pure 12 in 48% and 16 in 54% yield. Compounds 12 and 16 were then converted
into (1 ,2 )ꢀ2ꢀ(4ꢀbromophenyl)ꢀ2ꢀhydrazonoacetaldehyde oxime (13) and (1 ,2 )ꢀ2ꢀ(4ꢀ
chlorophenyl)ꢀ2ꢀhydrazonoacetaldehyde oxime (17) in 51% and 46% yield in a manner
analogous to the synthesis of compound , the only difference being that separation of the
ꢀ13 and ꢀ17 isomers by precipitation was achieved just by adding water, without
additional cooling. This was because the lower solubility of halogenated derivatives,
compared to nonꢀhalogenated ꢀ6 and ꢀ6, gives a mixture of isomers during cooled
precipitation; therefore, cooling was avoided. Obtained compounds ꢀ13 and ꢀ17 were
then reacted with 1,10ꢀphenanthrolineꢀ2,9ꢀdicarbaldehyde ( ) in the same manner as
5, but with additional purification by column chromatography
E
Z
E Z
6
Z
Z
Z
E
Z
Z
9
described for the product 11 via intermediates (14) and (18) respectively, obtained in 91%
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and 51% yield, to finally give 2,9ꢀbis(6ꢀ(4ꢀbromophenyl)ꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀ
5
6
phenanthroline
(
15)
and
2,9ꢀbis(6ꢀ(4ꢀchlorophenyl)ꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀ
7
8
9
phenanthroline (19) as a light orange to yellow powder in 88% (for 15) and 63% (for 19
)
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yield. Samples suitable for elemental analysis were obtained by recrystallization from
pyridine.
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As with the other syntheses, characterisation of the products (1HꢀNMR, CꢀNMR, IR,
MSꢀMALDI and elemental analysis,) confirmed their identities and showed that the
products 15 and 19 contain only 6,6ꢀsubstituted triazine in BTPhen without significant
quantities of byꢀproducts or impurities. Again, both IR and elemental analysis suggest the
presence of water in the solid state that cannot be removed by drying in vacuum.
General characteristic of the compounds 8, 11, 15 and 19
All obtained ligands are light yellow to orange microcrystalline powders with melting
points above 300°C, that are insoluble in water, as well as in most organic solvents
including hydrocarbons, alcohols, acetone, chlorinated hydrocarbons, acetonitrile, ethyl
acetate, etheric solvent such as THF, 1,4ꢀdioxane and diglyme. Solubility in DMF,
DMSO and pyridine is found to be limited at room temperature but improves
considerably when heated. Compound 11 was the most soluble – dissolves (5 mg/ml) in
warm DMF at 62°C. Compounds 15 (4BrPhBTPhen) and 19 (4ClPhBTPhen) were found
to be soluble in hot DMF (5 mg/ml at 112°C for 15 and 98°C for 19), DMSO (5 mg/ml at
110°C for 15 and 115°C for 19) and in pyridine (2.5 mg/ml at 105°C for 15 and 5 mg/ml
at 104°C for 19). The compounds are fully soluble in trifluoroacetic acid. Solubility
studies are summarised in Table 1 in ESI, Section 2. Elemental analysis suggests that the
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compounds 11, 15 and 16 are hygroscopic, while XRD shows compound 11 with a
molecule of solvent in the complexation cleft.
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Molecular structures of 8 (PhBTP) and 11 (PhBTPhen)
The product
8 was found to be in C2/c space group with Z = 4 and Z’ = 0.5. Suitable
single crystals were grown by slow cooling of saturated hot solution from 120°C to room
temperature over 72 hours in a NMR tube (the hotꢀbox technique). All crystallographic
details and data are given in ESI, Section 3.1.
Figure 2: An ORTEP diagram of the compound
8 (PhBTP) at 50% probability presenting
molecular structure.
Molecular structure of
8 (Figure 2) shows C2 symmetry around the crystal rotation axis
(symmetry code: ꢀx, y, 1/2ꢀz). The molecule is not planar; the triazine and phenyl rings
are rotated from the pyridine ring by 33.15(5)° and 46.14(6)° respectively. Due to C2
symmetry the triazine rings are related to each other by 49.24(5)° while the phenyl rings
are related by 58.80(5)°. The angle between two branches (C10ꢀCg1ꢀC10i, i = ꢀ x, y, 1/2ꢀ
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z, Cg1 = N1→C3i) is 110.21°, distance between C10 and C10i is 15.914 Å, while
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8
between C1 and C10 is 10.568 Å. In total, the solid state molecule of
shaped propeller. The main intermolecular interaction in crystal structure of the
compound is shown in Figure 3, while a detailed description of intermolecular
8 resembles a Vꢀ
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8
interactions is given in ESI, Section 3.1.
Figure 3: ORTEP diagram of the intermolecular interaction in solid compound
8 (PhBTP) at 50%
probability: two strong C2—H2···N4ii (C2···N4ii = 3.454(2) Å, ii = x,ꢀ1+y,z) interactions are
indicated.
Product 11 was found to be in C2/c space group with
Z = 8 and Z’ = 1, with a
disordered solvate of dimethylformamide in its cleft. The single crystals were also grown
in DMF using a “hotꢀbox” technique giving yellow, long plateꢀlike crystals. The selected
single crystal was found to be twined, with major component of 0.827(3) and minor of
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0.173(3). Twining was resolved by using TwinRotMat function included in the PLATON
software package.32 All crystallographic details and data are given in ESI, Section 3.2.
The molecular structure of 11 (Figure 4a) is also nonꢀplanar. In the phenanthroline core
rings A (N1ꢀC1ꢀC9ꢀC10ꢀC11ꢀC12) and B (N2ꢀC3ꢀC4ꢀC5ꢀC6ꢀC2) are twisted by angle of
12.67(0.25)°. The triazine ring T1 (C13ꢀN4ꢀN5ꢀC14ꢀC15ꢀN3) is related to the ring A by
24.44(13)°, while the phenyl ring P1 (C16→C21) is more coꢀplanar with the ring A
(4.97(27)°). In the opposite branch, the ring B and the triazine ring T2 (C22ꢀN7ꢀN8ꢀC24ꢀ
C23ꢀN6) are relatively coꢀplanar (9.15(0.32)°), whereas the phenyl ring P2 (C25→C30) is
rotated against the ring B by 22.22(27)°. The distances C8ꢀC18 and C7ꢀC28 are 12.534 Å
and 12.581 Å, respectively, while the distance C19ꢀC28 is 14.665 Å. Generally the two
branches of the molecule form an angle of 64.82(12)° (the angle between averaged
hypothetical lines C8ꢀC9ꢀC12ꢀC13ꢀC14ꢀC16ꢀC19 and C7ꢀC6ꢀC3ꢀC22ꢀC24ꢀC25ꢀC28) and
are distorted from planarity by 15.34(13)° (angle between two averaged hypothetical
planes: the ring A and the phenyl ring P1 versus the ring B and the triazine ring T2). In
total, the molecule has a slight helical form (Figure 4b).
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Figure 4: ORTEP diagrams of the compound 11 (PhBTPhen) at 50% probability presenting
molecular structure; a) phenanthroline rings A and B, T1 (triazine ring 1), T2 (triazine ring 2), P1
(phenyl ring 1), P2 (phenyl ring 2).
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The dimethylformamide molecule is found to be disordered with a major orientation
“S” (0.598(12) occupancy) and a minor orientation “R” rotated 180°C about a
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hypothetical axis along O1S and C1S atoms (nearly parallel with the cꢀaxis). The disorder
presumably arises from the clash between the atom N6 of the PhBTPhen molecule and
the methyl atom C3R. The solvent molecule resides in the cleft of the PhBTPhen
molecule and is bound to it via C3S—H3SC···N1 (C3S···N1 = 3.344(17) Å) interaction.
Oxygen atoms of both “S” and “R” orientations strongly interact with the neighbouring
PhBTPhen molecule and play important role in crystal structure formation by linking two
neighbouring PhBTPhen molecules (Figure 5). Detailed description of intermolecular
interaction is given in ESI, Section 3.2.
Figure 5: Solvent molecules form bridges across neighbouring PhBTPhen molecules and across the two
arms of a Vꢀshaped molecule via C—H···O/N interactions
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Molecular and crystal structures of 2ꢀhydrazonoꢀ2ꢀphenylacetaldehyde oxime (Zꢀ6 and Eꢀ
8
9
6) isomers
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As described, the isolated crystalline product
was formed during the reaction, as evidenced by thin layer chromatography of the
reaction solution. The ꢀ6 isomer was purified by column chromatography and the
6 was the Zꢀ6 isomer. The Eꢀ6 isomer
E
structures of both isomers determined using single crystal XRD. Lower solubility of the
ꢀ6 isomer is well known23,24 but our intention was
Zꢀ6 isomer in water compared to the E
to understand the cause of this phenomenon from their structures.
The ꢀ6 isomer aggregates in monoclinic system, space group P21/n (No.14). Bulk
Z
polycrystalline material readily crystallises from any solvent, however a single crystal
grown from CDCl3 was used for structure determination. Detailed crystallographic
parameters are listed in the ESI, Section 3.3.
Figure 6: An ORTEP diagram of
Zꢀ6 at 50% probability presenting molecular structure and the
internal N3—H3A···N1 hydrogen bonding.
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The most important feature of the
Zꢀ6 molecular structure (Figure 6) is the N3—
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H3A···N1 intramolecular hydrogen bond (N3···N1) = 2.7388(14) Å. This hydrogen bond
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is a direct consequence of the Zꢀconfiguration, where H3 atoms are in proximity to the N1
atom; this creates a 6ꢀmember ring (N1—C8—C7—N2—N3···H3), forming a stable
moiety. Conjugation of the C8=N1 and C7=N2 imine bonds additionally stabilises this
ring. The 6ꢀmember ring is nearly planar apart from the N1 atom that deviates from the
N3—N2—C7—C8 plane by approx. 15°. The phenyl ring is rotated from the N3—N2—
C7—C8 plane by approx. 35°. The N3—H3A···N1 internal hydrogen bonding and
consequent stable ring formation is likely the main reason why
Zꢀ6 is more lipophilic then
Eꢀ6 and therefore less soluble in water. Molecular packing diagram in the
Zꢀ6 solid is
shown in Figure 7. Detailed description of all relevant intermolecular interactions in
crystal structure is given in ESI, Section 3.3.
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Figure 7: Molecular packing diagram in the Zꢀ6 crystal, view along the bꢀaxis.
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A single crystal of the
E
ꢀ6 isomer was grown using the slow diffusion method
ꢀ6 in dichloromethane). It crystallises in a
(No.2) having two molecules (A and B) in the
Z’=2). Detailed crystallographic parameters are listed in the ESI,
(diffusion of diethyl ether into solution of
E
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ꢀ
P1
triclinic system, space group
asymmetric unit (
Section 3.4.
Figure 8: ORTEP diagrams of the molecules A and B of the Eꢀ6 crystal structure (50% probability
displacement ellipsoids).
Two molecules, A and B (Figure 8) have generally similar geometry, their main
difference being the degree of rotation of the phenyl ring relative to the near planar
backbones formed by N2—N1—C7—C8—N3—O1 atoms (the RMS deviation of fitted
atoms for hypothetical mean planes are 0.0378 for the molecule A and 0.0317 for the
molecule B). The C8—C7 bonds are 1.4592(17) Å and 1.4556(17) Å, which indicates
presence of N1=C7—C8=N3 conjugation. Two mean planes of the A and B backbones
are nearly parallel; they form an angle of 4.36(10)°. In the molecule A the phenyl ring
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(C1A→C6A) is rotated against the mean plane N2A—N1A—C7A—C8A—N3A—O1A
by average of 57.02(7)°, while the similar relation in the molecule B is 70.78(4)°.
Therefore, conjugation with adjacent N1=C7—C8=N3 is highly unlikely. Detailed
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description of all relevant intermolecular interactions in
ESI, Section 3.4.
Eꢀ6 crystal structure is given in
Crystallographic investigation of
Zꢀ6 and Eꢀ6 isomers showed that crystal packing of
both isomers (see ESI, Sections 3.3 and 3.4) is based on similar hydrogen bonding and is
even stronger in
(102ꢀ104°C) and
E
isomer than in
ꢀ6 (106ꢀ108°C) also suggest that lattice energies of both isomers are
ꢀ6 is the cause for higher
Z isomer. The similar melting points observed for Zꢀ6
E
similar. We conclude that intermolecular hydrogen bonding in
Z
hydrophobicity of the molecule (less strong dipole) and consequent lower water
solubility.
CONCLUSIONS
The extended Vꢀshaped BTPhen based ligands, PhBTPhen and 4XPhBTPhen (X = Br,
Cl), were successfully synthesised and a new reactantꢀdriven regioselective method for its
synthesis has been developed. The fiveꢀstep synthetic method proved to be simple, robust,
reproducible and reliable, giving only 6,6’ꢀphenyl substituted BTPhens in good yield. The
first two steps, preparation of reactants (1E,2Z)ꢀ2ꢀ(phenyl)ꢀ2ꢀhydrazonoacetaldehyde
oximes or hydrazones of isoꢀnitrosoacetophenones, are found to be lower yielding
(approx. 50% per step, total yield of 25%). Their advantage is they start with inexpensive,
commercially readily available acetophenones and reagents. The final two steps,
formation of 1,2,4ꢀtriazine rings, were found to be very high yielding (up to 91 and 88%,
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respectively) and avoid chromatographic purifications, nevertheless delivering a product
with high purity.
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Although this method for regioselective formation of substituted 1,2,4ꢀtriazine rings
has been used23ꢀ25 for preparation of 6,6ꢀphenyl BTP based derivatives, this is the first
time it was successfully applied to give phenanthroline (BTPhen) based compounds. The
mechanism of the 1,2,4ꢀtriazine ring cyclisation was explained in original work of
Kozhevnikov24 et al. and considered an E1cb elimination of water.
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The Vꢀshaped BTPhen derivatives prepared present an important entry point into of the
design of supramolecular ligands and systems based on BTPhen moiety as complexation
centre for the selective binding of minor actinides. Such ligands can be used for
sequestration of actinides for integration into selective sensors, for example.
Molecular and crystal analyses of PhBTP and PhBTPhen have confirmed the structure
and gave insight into the molecular geometry of these molecules and their intermolecular
interactions in solid state.
In addition, our investigation reveals molecular and crystal structures of
Z and E
isomers of hydrazones of isoꢀnitrosoacetophenones and helps to explain their simple
separation by change of solvent polarity utilized in the synthetic route to the Vꢀshaped
BTPhen derivatives. The existence of the N3—H3A···N1 internal hydrogen bond in the
isomer makes it more lipophilic and therefore less soluble in water.
Z
EXPERIMENTAL SECTION
General Information
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Thin layer chromatography (TLC) was performed on Silica Gel 60 F254 precoated plates. Spots
were visualized by UV light at 254 nm. Column chromatography was carried out using silica gel
(60 Å 230ꢀ400 mesh particle size, 40ꢀ63 mm). Infraꢀred (IR) spectra were recorded on a FTIR
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instrument on the neat compounds using an attenuated total reflection (ATR) accessory with a
1
diamond crystal. All wavenumbers (ν
̃
referenced to external tetramethylsilane via the residual protonated solvent (1H) or the solvent
itself (13C). All chemical shifts are reported in parts per million (ppm) while coupling constants
are reported in Hz. Abbreviations used in the description of resonances are: s (singlet), d
(doublet), t (triplet), br (broad), m (multiplet). Coupling constants (J) are quoted to the nearest
0.1 Hz. Assignments were made using 2D COSY and HSQC experiments. Highꢀresolution mass
spectra were recorded using electrospray ionization (ESI) on Agilent Technologies 1200 system
with Micromass QꢀTOF Micro™ detector and atmosphericꢀpressure chemical ionization (APCI)
on Agilent Technologies 1260 system with Micromass QꢀTOF Micro™ detector.
All spectra (1HꢀNMR, 13CꢀNMR, COSY, HSQC, IR and MS) are given in the Electronic
supporting information (ESI) file.
Pyridineꢀ2,6ꢀdicarboxamide (1)
Pyridineꢀ2,6ꢀdicaboxylic
acid
(6.0000 g,
35.92 mmol)
and
35 ml
(57.4000 g, 482.47 mmol, 13.5 equiv.) of thionyl chloride were refluxed in an oil bath at 85°C
overnight. Excess of thionyl chloride was distilled off to leave a dry, off white solid which was
then dissolved in dry toluene. The solution was then stirred in an ice bath while ethanol (12 ml)
was added over 15 minutes. The reaction mixture was then refluxed in an oil bath at 90 °C
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overnight. Thin layer chromatography confirmed that the reaction had gone to completion (Rf
[chloroform/ethyl acetate ꢀ 2:1] = 0.51). Product was purified by separation with sodium
carbonate solution (12 g in 100 ml) and the aqueous layers were washed with diethyl ether
(2×50 mL). The toluene and diethyl ether layers were combined and dried under vacuum to yield
a light pink powder. To this, concentrated aqueous ammonia (60 ml) was added and the mixture
stirred for 2 days. The product was filtered and dried to yield an offꢀwhite powder (4.9067 g,
yield: 83%). 1H NMR (400 MHz, DMSOꢀd6): δ 7.72 (2H, s), 8.12ꢀ8.20 (3H, m), 8.89 (2H, s); 13C
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NMR (100 MHz, DMSOꢀd6) δ 124.2, 139.2, 149.1, 165.4; IR (ATR): ν̃ 3395 (NꢀH), 3227 (NꢀH),
1661 (C=O), 1585 (C=C), 1568 (C=C); MS (ESI+): m/z 166.2 [M+H]+ (calcd for C7H7N3O2,
165.15); Expected for C7H7N3O2: % C, 50.91; H, 4.27; N, 25.44, found: % C, 51.17; H, 4.50; N,
25.10.
2ꢀPhenylglyoxal (2)
Acetophenone (1.10 ml, 1.1330 g, 9.43 mmol) was added to a stirred solution of selenium
dioxide (1.1465 g, 10.33 mmol, 1.1 equiv.) in 1,4ꢀdioxane/water (6.24 mL:0.84 mL) mixture,
and was refluxed in an oil bath at 80°C for 48 hours. The precipitate was filtered off over Celite
and the filtrate evaporated down to dryness to leave yellow oil. This was purified by column
chromatography using acetate/nꢀhexane (1:3 then 1:1) as eluent. Fractions were combined and
evaporated to give yellow oil; after 48 hours white crystals were formed
(0.3881 g, yield: 27.05 %). 1H NMR (400 MHz, CDCl3): mixture of two products, δ 4.96 (3H, d,
J = 10), 6.30 (3H, d, J = 10), 7.39ꢀ7.47 (14H, m), 7.55 (4H, t, J = 7.5), 7.61 (3H, t, J = 7.5), 8.05
(8H, d, J = 7.5), 8.13 (4H, d, J = 7.5), 9.60 (1H, s); MS (ESI+) m/z 135.1 [M+H]+ (calcd for
C8H6O2, 134.13). Expected for C8H6O2: % C, 63.15; H, 5.30; N, found: % C, 65.42; H, 5.16,
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analysis suggests that sample is a mixture of 2ꢀphenylglyoxal hydrate and 2ꢀphenylglyoxal in
ration 1:0.37: calcd. % C, 65.23; H, 15.12.
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Pyridineꢀ2,6ꢀdicarbaldehyde (3)
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Pyridineꢀ2,6ꢀdimethanol (1.9000 g, 13.70 mmol) and selenium dioxide (1.5150 g, 13.70 mmol,
1.0 equiv.) were dissolved in 1,4ꢀdioxane (30 ml) and refluxed for 5 h. The mixture was left to
cool and was filtered through a Celite pad before the solvent was evaporated. Thin layer
chromatography confirmed that the reaction was completed [Rf (hexane/ethylacetate ꢀ 3:1) =
0.286; Rf(CHCl3) = 0.259]. The crude product was purified using a dry loaded silica column
chromatography (eluent: hexane/ethyl acetate =3:1) to yield a pale orange, crystalline powder
1
(1.7800 g, yield: 75%). H NMR (400 MHz, CDCl3): δ 8.08 (1H, t, J = 7.6), 8.17 (2H, d, J =
7.6), δ 10.16 (2H, s); 13CꢀNMR (100MHz, CDCl3): δ 125.5, 138.5, 153.1, 192.5; IR (ATR):
ν̃
/cmꢀ1 3084 (CꢀH), 3017 (CꢀH), 2860 (CꢀH), 1715 (C=O), 1693 (C=N), 1580; MS (EI+) m/z
135.0 [M]+ (calcd for C7H5NO2, 135.05); Expected for C7H5NO2: % C, 62.22; H, 3.73; N, 10.34,
found: % C, 62.25; H, 3.55; N, 10.15.
2,6ꢀBis((E)ꢀhydrazonomethyl)pyridine (4)
Compound 3 (1.000 g, 7.40 mmol) was dissolved in warm, anhydrous ethanol (20 mL) and the
solution was added via a double ended needle to a solution of hydrazine monohydrate (0.75 ml,
15.54 mmol, 2.1 equiv.) in anhydrous ethanol (5 ml). The solution was left to stir for 3 h and
then cooled on ice for 15 minutes. The resulting product was filtered and washed with anhydrous
ethanol (7 ml) and diethyl ether (10 ml) yielding a white powder (0.9160 g, 76%). Thin layer
chromatography confirmed the product was formed (eluent: chloroform/methanol/NH4OH = 9 :
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1 : 0.105). 1H NMR (400 MHz, DMSOꢀd6) δ 7.19 (4H, s), 7.49 (2H, d, J = 8.0), 7.61 (1H, t, J =
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8.00), 7.67 (2H, s); C NMR (100 MHz, DMSOꢀd6): δ 116.0, 136.2, 138.1, 154.7; IR (ATR): ν
̃
3294 (NꢀH), 3127 (CꢀH Ar), 1637 (C=N), 1574 (CꢀC Ar); MS (ESI+): m/z 164.10 [M+H]+
(calcd for C7H9N5: 164.09); HRMS m/z for [M+Na]+ calcd 186.0756, found 186.0752; Expected
for C7H9N5: % C, 51.52; H, 5.56; 42.92, found: % C, 51.50; H, 5.71; 42.98.
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(E)ꢀ2ꢀOxoꢀ2ꢀphenylacetaldehyde oxime (5)
Acetophenone (2.33 ml, 2.4030 g, 20.00 mmol) was added drop wise to a solution of sodium
(0.4600 g, 20.00 mmol, 1.0 equiv.) in dry ethanol (20 ml) and the mixture was left to stir for 35
minutes. The mixture was cooled to 0°C and isoꢀpentyl nitrite (3.76 ml, 3.2800 g, 0.28 mmol)
was added drop wise. The mixture was stirred for 1 hour and left in the refrigerator for 72 h.
Then, diethyl ether (25 ml) was added and the precipitated solid was collected by filtration and
washed twice with diethyl ether (8 ml) and then dissolved in water (50 ml). Acetic acid was
added until pH 3 and the precipitated oxime was collected by filtration and dried to yield a pale
yellow to white crystalline product (0.8900 g, 30.0%). 1H NMR (400 Hz, DMSOꢀd6): δ 7.54 (2H,
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t, J =7.8), 7.67 (1H, t, J = 7.8), 7.98 (2H, d, J =7.8), 8.05 (1H, s), 12.70 (1H, s); C NMR (100
MHz, DMSOꢀd6): δ 128.4, 129.6, 133.2, 136.1, 147.7, 189.1; IR (ATR): ν̃ 3244 (OꢀH), 3071 (Cꢀ
H), 3009 (CꢀH), 2889 (CꢀH), 1674 (C=O), 1599(N=C), 1578(C=C); MS (ESIꢀ): m/z 149.932 [Mꢀ
H]ꢀ (calcd for C8H6NO2, 148.04); HRMS m/z for [M+H]+ calcd 150.0555, found 150.0561;
Expected for C8H7NO2 % C, 64.42; H, 4.73; N, 9.39, found: % C, 64.51; H, 4.68; N, 9.35.
(1E,2Z)ꢀ2ꢀHydrazonoꢀ2ꢀphenylacetaldehyde oxime (Zꢀ6)
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Compound 5 (0.8161 g, 5.47 mmol) was dissolved in dry ethanol (15 ml) and hydrazine
monohydrate (1.10 ml, 1.1352 g, 22.68 mmol, 4.00 equiv.) was added and left to stir for 28 h.
The completion of the reaction and disappearance of the starting material was monitored using
thin layer chromatography (ethyl acetate/hexane ꢀ 1:2). Water (35 mL) was then added and the
reaction mixture placed into an ice/acetone/NaCl bath (< ꢀ10 °C) for two hours during which
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precipitate was formed and then filtered and dried (0.4660 g, yield: 52%). H NMR (400 MHz,
DMSOꢀd6): δ 7.24(1H, t, J = 7.3), 7.33 (2H, t, J = 7.3), 7.54 (2H, d, J = 7.3), 8.29 (1H, s), 8.94
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(2H, s), 11.58 (1H, s); H NMR (400 MHz, CDCl3): δ 7.23(1H, t, J = 7.3 Hz), 7.29 (2H, t,
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J = 7.3 Hz), 7.45 (2H, d, J = 7.3 Hz), 7.94 (2H, br s) 8.16 (1H, s), 8.19 (1H, s); C NMR (100
MHz, CDCl3): δ 125.7, 127.7, 128.6, 133.0, 137.9, 146.8; IR (ATR): ν̃ 3331 (NꢀH), 3230 (OꢀH),
3026, 2843, 273, 1447; MS (ESI+): m/z 163.2 [M]+ (calcd for C8H9N3O, 163.18); HRMS
(ESI+): m/z for [M+Na]+ calcd 186.0643, found 186.0650; Expected for C8H9N3O: % C, 58.88;
H, 5.56; N, 25.75, found: % C, 58.47; H, 5.56; N, 25.65.
(1E,2E)ꢀ2ꢀHydrazonoꢀ2ꢀphenylacetaldehyde oxime (Eꢀ6)
The filtrate from the previous procedure was evaporated and obtained light yellow resin was
purified by column chromatography on silica using firstly ethyl acetate/hexane (1:3) and then
(1:2) to separate the Zꢀ6 (first fraction) and Eꢀ6 isomer (second fraction). Obtained yellow
compound Eꢀ6 was dried and characterised. 1H NMR (400 MHz, CDCl3): δ 5.70 (2H, br s), 7.12
(2H, dt, 3J = 7, 4J = 2), 7.35 (1H, tt, 3J = 7, 4J = 2), 7.42 (2H, tt, 3J = 7, 4J = 2), 7.82 (1H, s), 8.19
(1H, br s); 13C NMR (100 MHz, CDCl3): δ 128.5, 129.3, 129.5, 129.8, 144.4, 151.6; IR (ATR):
ν̃
3385, 3285, 3213, 3175, 3054, 2985, 2909, 1570, 1465; MS (ESI+) m/z 186.039 [M+Na]+
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(calcd for C8H9N3ONa, 186.06); HRMS (ESI+) m/z for [M+Na]+ calcd 186.0643, found
186.0643; Expected for C8H9N3O: % C, 58.88; H, 5.56; N, 25.75, found: % C, 59.33; H, 5.70; N,
25.55.
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2,6ꢀBis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)pyridine, PhBTP (8)
Compound 3 (0.070 g, 0.52 mmol) and compound Zꢀ6 (0.1800 g, 1.10 mmol, 2.1 equiv.) were
dissolved in ethanol (6 ml) and left to stir for 24 h. The formed yellow precipitate (compound 7)
was filtered, dried and weighed (0.2000 g, 90%). This was dissolved in acetic acid and left to
reflux for 1 hour, then the yellow crude was collected on a fritted funnel No.4 and washed twice
with water (5 ml). The crude was then recrystallized from DMSO to yield greenꢀyellow powder
(0.092 g, 45%). 1H NMR (500 MHz, TFAꢀd): δ 7.73 (4H, t, J =6), 7.80 (2H, d, J = 8), 8.29 (4H,
d, J = 6), 8.78 (1H, t, J = 6), 9.26 (2H, d, J = 6), 10.04 (2H, s); 13C NMR (500 MHz, TFA-d): δ
127.7, 128.0, 129.4, 130.0, 134.7, 143.9, 145.3, 155.0, 156.6, 158.6; IR (ATR): ν̃ 3079 (CꢀH),
3054 (CꢀH) 1463, 1290; MS (MALDI): m/z 390.775 [M+H]+ (calcd for C23H16N7, 390.15);
HRMS (APCI+): m/z for [M+H]+ calcd 390.1467, found 390.1456. Expected for C23H15N7: % C,
70.94; H, 3.88; N, 25.18; found: % C, 69.00; H, 3.65; N, 24.36; analysis suggests
C23H15N7×(H2O)0.48: calcd. % C, 69.39; H, 4.05; N, 24.63.
1,10ꢀPhenanthrolineꢀ2,9ꢀdicarbaldehyde (9)
Selenium dioxide (1.1620 g, 10.47 mmol, 2.1 equiv.) was dissolved in 1,4ꢀdioxane (25 ml) and
water (0.70 ml) and was heated to reflux. To this a solution of 2,9ꢀdimethylꢀ1,10ꢀphenanthroline
(1.0350 g, 4.97 mmol) in 1,4ꢀdioxane (20 ml) was added. The solution was heated under reflux
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for 30 minutes and the filtered when hot. The formed crystals were washed with 1,4ꢀdioxane and
chloroform before the obtained suspension was evaporated giving raw yield of 1.3000 g and
purified on silica (90 g) with dry loaded product (5 g silica) (eluent: DCM/MeOH = 9:1).
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Collected fractions were evaporated yielding a pale yellow powder (0.9981 g, 85%). H NMR
(400 MHz, CDCl3): δ 8.04 (2H, s), 8.38 (2H, d, J = 8.5), 8.50 (2H, d, J = 8.5), 10.55 (2H, s); 13C
NMR (100 MHz, CDCl3): δ 120.6, 129.1, 131.7, 138.1, 146.0, 152.8, 193.5; IR (ATR): ν̃ 3333
(HO), 3051 (CꢀH), 2851 (CꢀH), 2826 (CꢀH), 1700 (C=O); MS (APCI+): m/z 237.1 [M+H]+
(calcd for C14H8N2O2, 236.06); Expected for C14H8N2O2: % C, 71.18; H, 3.41; N, 11.86, found:
% C, 66.40; H, 3.80; N, 10.51; analysis suggests C14H8N2O2×(CH3OH)0.38×(H2O)0.68: calcd. %
C, 66.53; H, 4.19; N, 10.79.
2,9ꢀBis(6ꢀphenylꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthroline (11)
Compound 9 (0.1230 g, 0.52 mmol) was dissolved in 8.0 ml of methanol/chloroform blend (5: 3)
and added to compound Zꢀ6 (0.1800 mg, 1.10 mmol, 2.1 equiv.) dissolved in ethanol (2 ml). The
mixture was then left to stir for 24 hours at room temperature and the formed yellow precipitate
(compound 10) was filtered and dried (0.2100 mg, yield: 76%). The yellow precipitate (0.1343 g,
0.23 mmol) was then dissolved in acetic acid (10 mL) and the solution stirred under reflux at
90 °C for 1 hour. The formed product was filtered on a fritted funnel, washed with water twice
and dried to yield a yellow powder (0.0793 g, yield: 63 %). A sample for elemental analysis was
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prepared by recrystallization from DMSO. H NMR (500 MHz, TFA-d): δ 7.79 (4H, t, J = 7.4),
7.84 (2H, d, J = 7.4), 8.32 (4H, d, J = 6), 8.58 (2H, s), 9.38 (2H, d, J =7.4), 9.52 (2H, d, J =7.4),
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137.5, 145.0, 145.9, 154.6, 155.4, 158.6; IR (ATR): ν
̃
3410 (OꢀH), 3039 (CꢀH), 1491, 1442,
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1390; MS (MALDI): m/z 490.922 [M+H]+ (calcd for C30H19N8, 491.17), 512.962 [M+Na]+
(calcd for C30H18N8Na, 513.16): HRMS (APCI+): m/z for [M+H]+ calcd 491.1733, found
491.1738. Expected for C30H18N8: % C, 73.46; H, 3.70; N, 22.84, found: % C, 68.09; H, 3.92; N,
20.81; analysis suggests C30H18N8×(C2H6OS)0.5×(H2O)0.9: calcd. % C, 68.21; H, 4.22; N: 20.53.
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(E)ꢀ2ꢀ(4ꢀBromophenyl)ꢀ2ꢀoxoacetaldehyde oxime (12)
4ꢀBromoacetophenone (4.5800 g, 20.00 mmol) was dissolved in dry ethanol (8 ml) and added
dropwise to a solution of sodium (0.4600 g, 20.00 mmol) in dry ethanol (12 mL). The mixture
was left to stir at room temperature for 35 minutes then 3.76 ml (3.2800 g, 56.00 mmol, 1.4
equiv.) of isoꢀpentyl nitrate was added and left to stir for 1h then left in the fridge for 72 hours.
After this diethyl ether (30 ml) was added to the deep red suspension and it was left for 30
minutes. The mixture was filtered and the precipitated solid was twice washed with diethyl ether
(30 ml), dried, and then dissolved in water (70ꢀ80 ml). Undissolved red impurities were filtered
off and acetic acid was added till pH 3. The formed suspension was filtered, then obtained
yellow paste was reꢀdissolved in diethyl ether (100 ml), excess of water was removed with a
Pasteur pipette and the solution was dried by the addition of anhydrous MgSO4 and filtered. The
diethyl ether was then removed by rotaꢀevaporation and the product was then left to dry for 24
hours in a vacuum chamber yielding a yellow powder (2.9700 g, 58%). Since thin layer
chromatography was found raw product not to be pure it was purified by column
chromatography on silica (100 g) (eluent: nꢀhexane/ethyl acetate = 3:1 then 2:1). The final yield
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of the pure product was 2.4500 g (48%). H NMR (400 MHz, DMSOꢀd6) δ 7.76 (2H, dt, J = 9,
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δ 127.8, 131.9, 132.1, 135.5, 148.2, 188.6; IR (ATR): ν̃ 3213 (OꢀH), 3093 (CꢀH), 1672 (C=O),
1583, 1417, 985 (NꢀO); MS (ESIꢀ): m/z 225.884 [M]ꢀ (calcd for C8H5NO2Br, 225.95); HRMS
(ESI+) m/z for [M+Na]+ calcd 249.9480, found 249.9477. Expected for C8H6NO2Br: % C,
42.14; H, 2.65; N, 6.14; Br, 35.04, found: % C, 42.39; H, 2.73; N, 6.08; Br, 35.10.
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(1E,2Z)ꢀ2ꢀ(4ꢀBromophenyl)ꢀ2ꢀhydrazonoacetaldehyde oxime (13)
Compound 12 (2.2585 g, 9.90 mmol) was dissolved in dry ethanol (50 ml) in a 250 ml roundꢀ
bottom flask and 2.4 ml (2.4900 g, 49.50 mmol, 5.0 equiv.) of hydrazine monohydrate was
added. The reaction was then left to stir for 24 hours and completion of the reaction was
monitored using thin layer chromatography (nꢀhexane/ethyl acetate = 2:1). Water (115 ml) was
then added to crystallise out the product, which was then filtered and dried. This yielded a white
crystalline solid (1.2218 g, yield: 51 %). 1H NMR (400 MHz, CDCl3) δ 7.40 (2H, dt, 3J = 4, 4J =
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2), 7.48 (2H, dt, J = 4, J = 2), 7.75 (1H, s), 8.08 (2H, s), 8.22 (1H, s); C NMR (100 MHz,
CDCl3) δ 121.6, 127.1, 131.2, 131.6, 136.9, 146.3; IR (ATR): ν 3275 (OꢀH), 3128 (NꢀH), 2854,
̃
1589, 1468; MS (ESI+) m/z 241.959 [M+H]+ (calcd for C8H9N3OBr, 241.99); HRMS (ESI+)
m/z for [M+H]+ calcd 241.9929, found 241.9939; Expected for C8H8N3OBr: % C, 39.69; H,
3.33; N, 17.36; Br, 33.01, found: % C, 39.69; H, 3.12; N, 17.14; Br, 33.88.
2,9ꢀBis(6ꢀ(4ꢀbromophenyl)ꢀ1,2,4ꢀtriazinꢀ3ꢀyl)ꢀ1,10ꢀphenanthroline (15)
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Compound 9 (0.6310 g, 2.67 mmol) was dissolved in dichloromethane (31 ml) in a 100 ml
roundꢀbottom flask. Compound 12 (1.3570 g, 5.60 mmol, 2.1 equiv.) was dissolved in
dichloromethane (55 ml) and the solution was added into the flask with compound 9 via doubleꢀ
ended needle. The mixture was left to stir at room temperature for 27 hours. After this time the
formed yellow precipitate (compound 14) was filtered and dried (1.6400 g, yield: 90%) before it
was crushed into powder and suspended in acetic acid (50 ml). The suspension was placed onto
an oil bath at 65°C where the temperature was then raised to 90°C. It was left to stir at 90°C for
65 minutes, and then it was cooled, filtered on a fritted funnel No.5, rinsed once with acetic acid
(5 mL), and several times water (10 ml) until pH of the filtrate was neutral, dried under vacuum
for 24 hours giving pale orange powder (1.3800 g, yield: 88%). A sample for elemental analysis
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was obtained by recrystallization from pyridine. H NMR (500 MHz, TFAꢀd) δ 7.97 (4H, d, J =
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7), 8.23 (4H, d, J = 7), 8.61 (2H, s), 9.41 (2H, d, J = 8), 9.54 (2H, d, J =8), 9.98 (2H, s); C
NMR (100 MHz, TFAꢀd) δ 125.6, 127.8, 129.0, 129.8, 130.2, 133.2, 133.5, 137.6, 145.0, 146.0,
153.9, 155.5, 157.9. IR (ATR): ν̃ 3418 (OꢀHwater), 3093 (CꢀH), 3051 (CꢀH), 1589, 1391, 613 (Cꢀ
Br); MS (MALDI) m/z 670.959 [M+Na]+ (calcd for C30H16 Br2N8Na, 670.97), HRMS (APCI+)
m/z for [M+H]+ calcd 648.9920, found 648.9994; Expected for C30H16Br2N8: % C, 55.58; H,
2.49; ; N, 17.28, found: % C, 54.79; H, 2.34; ; N, 16.81; analysis suggests
C30H16Br2N8×(H2O)0.5: calcd. % C, 54.81; H, 2.61; N, 17.05.
(E)ꢀ2ꢀ(4ꢀChlorophenyl)ꢀ2ꢀoxoacetaldehyde oxime (16)
4ꢀChloroacetophenone (2.6 ml, 3.0920 g, 20.00 mmol) was added dropꢀwise to a stirred solution
of sodium (0.4600 g, 20.00 mmol) in dry ethanol (20 ml) under nitrogen and the reaction mixture
was stirred for 35 minutes at room temperature. Isoꢀpentyl nitrite (3.8 ml, 3.3140 g, 28.28 mmol,
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