Experimental and computational study on the reactivity of 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile, a key intermediate for the synthesis of tribenzoporphyrazine bearing peripheral methyl(3-pyridylmethyl)amino substituents

Article abstract of DOI:10.1007/s00706-011-0503-9

An earlier developed alkylating path leading to tetraalkylated diaminomaleonitrile derivatives was explored. Attempts to explain the reactivity of the representative dialkylated diaminomaleonitrile 2,3-bis[(3-pyridylmethyl) amino]-2(Z)-butene-1,4-dinitril

Full text of DOI:10.1007/s00706-011-0503-9

Monatsh Chem (2011) 142:599–608
DOI 10.1007/s00706-011-0503-9
ORIGINAL PAPER
Experimental and computational study on the reactivity
of 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile,
a key intermediate for the synthesis of tribenzoporphyrazine
bearing peripheral methyl(3-pyridylmethyl)amino substituents
•
Tomasz Goslinski Zbigniew Dutkiewicz Michal Kryjewski Ewa Tykarska
•
•
•
•
Lukasz Sobotta Wojciech Szczolko Maria Gdaniec Jadwiga Mielcarek
•
•
Received: 9 July 2010 / Accepted: 2 April 2011 / Published online: 4 May 2011
Ó The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract An earlier developed alkylating path leading
to tetraalkylated diaminomaleonitrile derivatives was explo-
red. Attempts to explain the reactivity of the representative
dialkylated diaminomaleonitrile 2,3-bis[(3-pyridylmethyl)-
amino]-2(Z)-butene-1,4-dinitrile during the alkylation
reaction were performed using X-ray and density functional
theory (DFT) studies. The condensed Fukui functions
accompanied by softness indices were found to be useful in
explaining its reactivity observed during the reaction. The
values of the Fukui functions and condensed softness for
ted dinitrile 2,3-bis[methyl(3-pyridylmethyl)amino]-2(Z)-
butene-1,4-dinitrile was used in the synthesis of tribenzo-
porphyrazine bearing methyl(3-pyridylmethyl)amino groups,
which was subsequently subjected to solvatochromic and
metallation studies. The changes observed during metallation
seem to result from the coordination of the 3-pyridyl group by
a palladium ion. This could influence the configuration of the
methyl(3-pyridylmethyl)amino moiety, causing more effec-
tive donation of a lone pair of electrons from peripheral
nitrogen to the macrocyclic ring.
¨
electrophilic attack calculated from Mulliken, Lowdin, and
natural population analyses closely corresponded to the
experimental observations. When 2,3-bis[(3-pyridyl-
methyl)amino]-2(Z)-butene-1,4-dinitrile disodium salt was
treated with dimethyl sulfate at lower temperatures the
alkylation reaction prevailed, whereas at higher tempera-
tures the alkylating agent acted as a hydride anion acceptor,
which favored the elimination reaction. The tetraalkyla-
Keywords Alkylations ꢀ Density functional theory ꢀ
Diaminomaleonitrile ꢀ Tribenzoporphyrazine ꢀ
X-ray structure determination
Introduction
Diaminomaleonitrile (DAMN) and its derivatives have
received much attention in recent years and have been
extensively used in synthesis of amino-functionalized mac-
rocycles and many other imine and imidazole compounds,
pyrazines, pyrimidines, purines, azepines, pyrroles, oxaz-
oles, nucleosides, and in photosynthesis of 4-amino-5-
cyanoimidazole [1–7]. Tetraalkylated derivatives of DAMN
are key substrates for synthesis of porphyrazines, including
tribenzoporphyrazines bearing amino moieties. Peripheral
amino groups provide these electron-rich macrocycles with
unusual optical and electrochemical properties. They exhibit
unusual coordination properties because of two metal ion
binding sites—within the central cavity and by the peripheral
amino moieties [3].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0503-9) contains supplementary
material, which is available to authorized users.
T. Goslinski (&) ꢀ Z. Dutkiewicz ꢀ E. Tykarska ꢀ W. Szczolko
Department of Chemical Technology of Drugs,
Poznan University of Medical Sciences, Grunwaldzka 6,
60-780 Poznan, Poland
e-mail: tomasz.goslinski@ump.edu.pl
M. Gdaniec
Faculty of Chemistry, Adam Mickiewicz University,
Grunwaldzka 6, 60-780 Poznan, Poland
M. Kryjewski ꢀ L. Sobotta ꢀ J. Mielcarek
Department of Inorganic and Analytical Chemistry,
Poznan University of Medical Sciences, Grunwaldzka 6,
60-780 Poznan, Poland
Porphyrins and related macrocycles, including por-
phyrazines bearing peripheral pyridyl substituents for self-
assembly by metal ion coordination, have been widely
123

600
T. Goslinski et al.
studied as molecular building blocks for creating super-
molecular structures for potential use in nanotechnology
[8, 9]. Many of the 2- and 4-pyridyl substituted macrocy-
cles revealed excellent metal ion binding properties
[10–13]. Methyl(2-pyridylmethyl)amino substituted tri-
benzoporphyrazines have shown excellent metal-binding
abilities [3]. Macrocycles with a peripheral 3-pyridyl sub-
stituent have been little studied so far [14, 15], whereas
porphyrazines substituted in the periphery with mixed
methyl(3-pyridylmethyl)amino and 2,5-dimethylpyrrolyl
ligands have revealed selective coordination properties
[16]. In view of our work on synthesis and physicochem-
ical studies of porphyrazines and tribenzoporphyrazines
carrying peripheral methyl(3-pyridylmethyl)amino substit-
uents, it appeared useful to investigate the spectroscopic
properties of the metallated and unmetallated methyl(3-
pyridylmethyl)amino moieties.
have been observed. Moreover, synthesis of imine has been
noted during palladium-catalyzed alkylation of dibenzyl
diaminomaleonitrile using methyl chloroacetate and the
synthesis of acetic acid functionalized dibenzyl diamino-
maleonitrile [4]. We aimed to address the cause of the
reactivity of dialkylated DAMN derivatives and attempted to
explain it using quantum chemical calculations.
Results and discussion
Synthesis
Sequential double-reductive alkylation of DAMN (1, Fig. 1)
was employed to yield 2,3-bis[(3-pyridylmethyl)amino]-
2(Z)-butene-1,4-dinitrile (5) following a method elaborated
by the Sheppard [1] and Barrett–Hoffman teams [3]. The
intermediates 2-amino-3-[(3-pyridylmethylidene)amino]-
2(Z)-butene-1,4-dinitrile (2) and 2-amino-3-[(3-pyridyl-
methyl)amino]-2(Z)-butene-1,4-dinitrile (3) have been
previously obtained and characterized [16]. It was found that
alkylation reaction of 5 using dimethyl sulfate in the pres-
ence of sodium hydride in the temperature range -20 to
-10 °C led to the alkylated 2,3-bis[methyl(3-pyridyl-
methyl)amino]-2(Z)-butene-1,4-dinitrile (6) with 13% yield.
The product was isolated as red–brown oil, which was very
unstable during attempted crystallization. Moreover, when
the reaction was performed at 0 °C, imine 2-[(3-pyri-
dylmethyl)amino]-3-[(3-pyridylmethylidene)amino]-2(Z)-
butene-1,4-dinitrile (4) was isolated alone or in the mixture
of products, yielding up to 45%. Attempts to elucidate this
observation are reported later in this paper.
During the synthesis of a tetraalkylated DAMN derivative
from a dialkylated precursor, undesired side-reactions took
place, leading mainly to imine precursor formation. We
further investigated this reaction in more detail using DFT
studies. Imine product formation has been described in lit-
erature in various experiments performed on a dibenzyl
DAMN derivative. Sheppard and coworkers have shown that
2,3-bis(benzylamino)-2(Z)-butene-1,4-dinitrile may be oxi-
dized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) to dibenzyldiiminosuccinonitrile, which subse-
quently isomerizes to 2-benzylamino-3-benzylideneamino-
2(Z)-butene-1,4-dinitrile [1]. Alkylation studies using a
broad range of alkylating agents and bases, performed by
Barrett, Hoffman, and coworkers on a dibenzyl DAMN
derivative, indicated that in some reaction conditions this
compound might act more like a hydride anion donor than a
nucleophile. As a result, a reduced yield of tetraalkylated
dinitrile, isolation of dinitrile isomers, or imine formation
Linstead macrocyclization of tetraalkylated DAMN
derivative 6 (magnesium butanolate in butanol) led in low
yield to a symmetrical porphyrazine, which was hardly
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH2
NH2
NH
N
NH
NH
N
NH
NaBH4
MeOH
NaBH4
MeOH
O
O
MeOH
TFA (cat)
MeOH
NH2
NH2
TFA (cat)
N
N
1
2
3
4
5
R
R
R
R
N
R
R
F
N
N
R
R
R
R
N
N
N
N
O
O
Zn(OAc)2
DBU
N
N
N
N
N
N
N
N
N
Me2SO4
Zn
N
Zn
N
N
N
N
+
N
+
N
DMF
NaH
PeOH
N
N
N
N
F
N
R
R
R
R
R=
F
O
6
7
8
9
Fig. 1 Synthesis of dinitriles 4–6, tribenzoporphyrazine 8, and phthalocyanine 9. TFA trifluoroacetic acid
123

Experimental and computational study on the reactivity of amino substituents
601
soluble and therefore difficult to purify [17]. The new
hydroquinone dialkyl ether 3,6-bis(4-fluorobutoxy)ben-
zene-1,2-dicarbonitrile (7) was synthesized by modifying
the method of 2,3-dicyanohydroquinone alkylation [18]. A
mixed macrocyclization reaction of dinitriles 6 and 7 in
pentanol using zinc acetate and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) as a base was employed to synthesize
1,4,8,11,15,18-hexakis(4-fluorobutoxy)-22,23-bis[methyl-
(3-pyridylmethyl)amino]tribenzo[b,g,l]porphyrazinatozinc
(II) (8) and [1,4,8,11,15,18,22,25-octakis(4-fluorobutoxy)-
phthalocyanato]zinc(II) (9). Compound 8 appeared to
possess good solubility in common organic solvents due
to the presence of lipophilic 4-fluorobutoxy groups in
nonperipheral positions. The structures of tribenzopor-
phyrazine 8 and phthalocyanine 9 were elucidated using
nuclear magnetic resonance (NMR) data and are discussed
in the Supplementary Material.
packing and molecular conformations, as the crystals of
these two compounds are isostructural.
In compounds 4 and 5 the amino N atom in part A has
planar sp2 hybridization and all atoms bonded to N8A are
coplanar with the maleonitrile fragment [the torsion angle
C7A-N8A-C2-C3 is -173.6(1)° and -171.4(1)° for 4 and
5, respectively]. Thus, there is significant involvement of
the amino N lone pair of electrons with the p-system of the
maleonitrile unit, which results in shortening of the for-
mally single N8A-C2 bond [the bond distance is 1.346(2)
˚
˚
A in 4 and 1.359(1) A in 5]. In the chemically symmetrical
compound 5 both parts, A and B, of the molecule are
structurally different, because the amino N8B atom in
part B has sp3 hybridization. The sp2 hybridization of the
two amino N atoms would result in steric hindrance
between the two amino hydrogens, and the relief of the
strain in 5 is achieved by pyramidalization of one of the
enamine N atoms (N8B), giving rise to the reduction of
conjugation between the electron lone pair of the amino
nitrogen and the double-bond p electrons. This fact is
reflected in a significant lengthening of the Csp2-N bond to
Attempts to explain the alkylation reaction of 5
on the basis of crystal structure analysis
and quantum chemical calculation
˚
this amino group [C3-N8B 1.408(2) A]. In compound 4 the
The imine product formation observed during the course of
experiments was explained by crystal structure analysis of
dinitriles 4 and 5 and quantum chemical calculations of
dinitrile 5. The structures of both dinitriles 4 and 5 deter-
mined by X-ray crystallography (Fig. 2) show that the
chemical modification from the imine group in 4 to the
amine group in 5 had virtually no effect on the crystal
p-electron delocalization occurs over a larger part of the
molecule than in 5 because it additionally includes
the imine –N=C– fragment and the pyridine ring. In 4 the
imine group is conjugated not only with the maleonitrile
fragment but also with the pyridine ring, and this explains
why the corresponding Csp2-Nsp2 and Csp2-Nsp3 bond
Fig. 2 X-ray structures of
dinitriles 4 and 5 showing the
atom-labeling scheme.
Displacement ellipsoids are
drawn at the 50% probability
level, and H atoms are shown as
spheres of arbitrary radius
123

602
T. Goslinski et al.
lengths in 4 and 5 are virtually the same [C3-N8B
phase. These optimizations were followed by vibration
frequency calculations to ensure that all four conformations
were true minima on the potential-energy surface
(Table 5S, Supplementary Material).
˚
1.392(2) A in 4 and 1.408(2) A in 5].
˚
X-ray data showing inequivalence of the two sides of
dinitrile 5 in the solid state have pleasingly corresponded to
literature quantum mechanical calculations of the rotational
barriers in diaminomaleonitrile performed by Dwyer et al.
[19]. DAMN is able to achieve stability by rotating one
amino group of the heavy atom plane by 90° so that the
amino hydrogens lie above and below the aforementioned
plane and conjugating a single N lone pair into the C=C p
system. What has been found interesting in the minimum-
energy structure of DAMN is that the amino nitrogens are
pyramidal and the C–N bond of the twisted amino group is
The condensed Fukui functions were applied to explain
both reaction paths observed during alkylation reaction of
5, one being alkylation to 6 and the other being formation
of imine 4. The selected values for the Fukui functions fkꢁ,
fkþ, and fk0 and condensed softness skꢁ(skꢁ ¼ Sfkꢁ) for elec-
trophilic attack were calculated from Mulliken (MPA),
¨
Lowdin (LPA), and natural population (NPA) analyses and
are presented in Table 1 (complete data Tables 6S–9S,
Supplementary Material) [20].
˚
0.04 A longer than the C–N bond which is coplanar with
DFT calculations indicate that both sides of dinitrile
disodium salt 5-Na are identically or almost identically
traceable for alkylating agents (Fig. 3). The values of the
sꢁk indices for N8A and N8B are in the ranges 0.159–
0.477, 0.234–0.723, and 0.559–1.093 in accordance with
MPA, LPA, and NPA analyses, respectively. What is
interesting is that these indices obtained using MPA, LPA,
and NPA analyses for H71A, H72A, H71B, and H72B had
the following values: 0.102–0.293, 0.044–0.172, and
0.057–0.209. These condensed softness values clearly
indicate the overall tendency of the alkylation reaction to
be dominant (sꢁk values for N8A and N8B), which is
particularly pronounced in the NPA and LPA analyses.
Nevertheless, it might be presumed that, at higher tem-
perature, especially for unsymmetrical conformers, the
elimination reaction might take place (sꢁk values for H71A,
H72A and H71B, H72B). Moreover, the overall tendency
for the elimination reaction to proceed, based on the ratios
of sꢁk values for H71A, H72A to N8A and H71B, H72B to
N8B, is more marked for unsymmetrical conformers
than for symmetrical ones (Table 10S, Supplementary
Material).
the maleonitrile part. The minimum-energy structure of
DAMN implies that the most stable geometry involves
delocalization of a lone pair from a single nitrogen. We
consider that this may generally explain the observed in-
equivalence of the two DAMN amine groups during
reductive alkylation and force the sequential double-
reductive alkylation of DAMN in the synthetic path.
Our DFT studies were performed in order to explore the
reactivity of 5 during alkylation reaction. Optimizations of
molecular structures of 5 in the form of its disodium salt
(5-Na) at the B3LYP/6-31G(d,p) level were preceded by
conformational study of 5 in vacuo at the B3LYP/6-
31G(d,p) level. As a result of this search, more than 100
conformations were found for 5, in which 26 groups of
conformers were identified. These conformers possessed
dihedral angles of very similar values within the same
group: a1 (C3-C2-N8A-C7A), a2 (C2-C3-N8B-C7B), b1
(C2-N8A-C7A-C1A), b2 (C3-N8B-C7B-C1B), and four
different sets of angles describing 3-pyridyl ring rotation c1
(N8A-C7A-C1A-C6A) and c2 (N8B-C7B-C1B-C6B). In
almost all conformations the molecular frame (DAMN
moiety with CH2 groups) was found to possess C1 sym-
metry, with the exception of two conformations for which
C2 symmetry appeared and the other two for which the
symmetry of the molecular frame was very close to C2 (the
same group of four conformations with similar values of
a1, a2, b1, and b2).
The calculated data pleasingly correspond to the
experimental observations. When dinitrile 5-Na was trea-
ted with dimethyl sulfate at lower temperature the
alkylation reaction prevailed, whereas at higher tempera-
ture the alkylating agent acted as hydride anion acceptor,
which favored the elimination reaction.
In the next step, three conformations of 5 found in the
conformational study were selected: the unsymmetrical
conformation with the lowest energy (C1 symmetry),
another unsymmetrical conformation (the energy of which
is higher than that found for the previous conformation but
lower than that of the optimized X-ray structure), and a
symmetrical conformation (C2 symmetry). The optimized
X-ray structure of 5 was selected as the fourth conforma-
tion for further study. Hydrogen atoms H8A and H8B in
these four conformers of dinitrile 5 were replaced with
sodium atoms to give the corresponding sodium salts (5-
Na1–5Na4), which were subsequently optimized in the gas
Spectroscopic and solvatochromic studies
Since the heteroatoms present at the b positions of por-
phyrazines and tribenzoporphyrazines are in direct
electronic contact with the macrocyclic core p system, the
binding of metal ions is evidenced by profound changes in
their UV–Vis spectra. The research previously performed
on metalloporphyrazines functionalized with heteroatoms
coordinating additional metal ions has opened the way to
the applications of these compounds as sensors, which have
been demonstrated so far for, e.g., pzs bearing peripheral
123

Experimental and computational study on the reactivity of amino substituents
603
Table 1 Condensed Fukui functions and softness indices sꢁk for 5-Na calculated from Mulliken, Lowdin, and natural population analyses at
B3LYP/6-31G(d,p) level
¨
5-Na1
5-Na2
5-Na3
5-Na4
5-Na1
5-Na2
5-Na3
5-Na4
MPA fꢁ ðSꢁÞ
N8A
0.089
0.091
0.070
0.067
N8B
0.036
0.032
0.070
0.067
(0.477)
-0.048
(-0.257)
0.053
(0.454)
-0.030
(-0. 150)
0.055
(0.364)
-0.030
(-0.157)
0.048
(0.360)
-0.029
(-0.158)
0.048
(0.195)
-0.039
(-0.208)
0.047
(0.159)
-0.034
(-0.171)
0.047
(0.363)
-0.030
(-0.158)
0.044
(0.361)
-0.029
(-0.158)
0.048
C7A
C7B
H71A
H72A
H71B
H72B
(0.285)
0.055
(0.273)
0.040
(0.249)
0.044
(0.256)
0.043
(0.251)
0.035
(0.234)
0.020
(0.228)
0.048
(0.256)
0.043
(0.293)
(0.202)
(0.228)
(0.230)
(0.188)
(0.102)
(0.249)
(0.230)
LPA fꢁ ðSꢁÞ
N8A
0.135
(0.723)
-0.001
(-0.007)
0.030
0.134
(0.668)
0.003
0.106
(0.550)
0.002
0.100
(0.536)
0.002
N8B
0.057
(0.305)
0.006
0.047
(0.234)
0.009
0.106
(0.548)
0.002
0.100
(0.537)
0.002
C7A
C7B
(0.013)
0.029
(0.009)
0.022
(0.013)
0.022
(0.031)
0.022
(0.044)
0.021
(0.009)
0.023
(0.013)
0.022
H71A
H72A
H71B
H72B
(0.159)
0.032
(0.145)
0.019
(0.114)
0.023
(0.118)
0.022
(0.116)
0.017
(0.105)
0.009
(0.118)
0.022
(0.118)
0.021
(0.172)
(0.094)
(0.118)
(0.116)
(0.089)
(0.044)
(0.114)
(0.116)
NPA fꢁ ðSꢁÞ
N8A
0.204
(1.093)
-0.027
(-0.146)
0.036
0.195
(0.973)
-0.020
(-0.102)
0.034
0.191
(0.993)
-0.022
(-0.113)
0.027
0.185
(0.997)
-0.021
(-0.113)
0.027
N8B
0.128
(0.687)
-0.018
(-0.096)
0.027
0.112
(0.559)
-0.010
(-0.051)
0.028
0.191
(0.991)
-0.022
(-0.113)
0.028
0.185
(0.997)
-0.021
(-0.113)
0.027
C7A
C7B
H71A
H72A
H71B
H72B
(0.192)
0.039
(0.170)
0.022
(0.139)
0.028
(0.143)
0.026
(0.144)
0.022
(0.138)
0.011
(0.144)
0.027
(0.143)
0.026
(0.209)
(0.112)
(0.144)
(0.142)
(0.115)
(0.057)
(0.138)
(0.141)
Softness indices (in au-1) are given in parentheses
diaza-18-crown-6 ring systems and N-methyl-(2-pyridyl-
methyl)amino units [3, 21].
pyridylmethyl)-PdCl2 bonded fragment. Titration with
Pd(II) resulted in a less intensive decrease in the Soret band
and a more intensive Q-band absorption that continued
through a Pd(II)-ligand ratio of ca. 1 (Fig. 4). Additionally
a large red-shift of the Q-band by 120 nm together with a
shift of the n-p* peak to ca. 560 nm were observed. We
propose that the changes observed during metallation are
due to the coordination of the 3-pyridyl group by a palla-
dium ion, which may change the configuration of the
methyl(3-pyridylmethyl)amino moiety, causing more
effective donation of a lone pair of electrons from
peripheral nitrogen to the macrocyclic ring. This proposi-
tion is based on the fact that the n-p* band in the UV–Vis
spectrum of tribenzoporphyrazine did not occur before, but
after the metallation. Unfortunately, this complex appeared
to be very sensitive to light and oxygen, as its photoble-
aching slowly occurred and it was not possible to obtain
crystals suitable for X-ray measurements.
UV–Vis spectroscopy was employed to evaluate solva-
tochromic effects of 8 and 9. In dichloromethane:methanol
(1:1) solution, tribenzoporphyrazine 8 exhibits a Soret peak
at 332 nm and Q-band at 730 nm with shoulders at 660 and
810 nm. Solvatochromic studies performed on 8 (Fig. 4)
and 9 (Fig. 11S, Supplementary Material) in various
aprotic and protic solvents revealed the Q-band changes in
the range from 723 nm (acetonitrile) to 736 nm (pyridine)
[22, 23]. The Q-band wavelength is better correlated to the
refractive index than the dipole moment for 8 and 9
(Table 2), suggesting that the red-shift is due to solvation
rather than coordination.
Tribenzoporphyrazine 8 was further subjected to titra-
tion with palladium ions, showing significant changes in
the UV–Vis profile, probably due to heterobimetallic por-
phyrazine product formation carrying the exocyclic di(3-
123

604
T. Goslinski et al.
Fig. 3 Optimized structures of dinitrile 5-Na derived from: a the
lowest-energy conformation of dinitrile 5-Na1; b one of the C1-
symmetry conformations of dinitrile 5-Na2; c one of the C2-symmetry
conformations of dinitrile 5-Na3; d optimized X-ray conformation of
dinitrile 5-Na4
c
Conclusions
A previously developed alkylating path leading to tetra-
alkylated diaminomaleonitrile derivatives was examined.
An attempt to explain the reactivity of the representative
dialkylated diaminomaleonitrile 2,3-bis[(3-pyridylmethyl)-
amino]-2(Z)-butene-1,4-dinitrile during alkylation reaction
was performed using X-ray and DFT studies. The con-
densed Fukui functions accompanied by softness indices
appeared to be useful in the explanation of both routes of
the observed alkylation reaction. The values of the Fukui
functions and condensed softness for electrophilic attack
¨
calculated from Mulliken, Lowdin, and natural population
analyses closely correspond to the experimental observa-
tions. When 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-
1,4-dinitrile disodium salt was treated with dimethyl sulfate
at lower temperatures the alkylation reaction prevailed,
whereas at higher temperatures the alkylating agent acted
as hydride anion acceptor, which favored the elimination
reaction. The tetraalkylated dinitrile 2,3-bis[methyl(3-pyr-
idylmethyl)amino]-2(Z)-butene-1,4-dinitrile was used in
the synthesis of tribenzoporphyrazine bearing methyl(3-
pyridylmethyl)amino groups, which was subsequently
subjected to solvatochromic and metallation studies. The
changes observed during metallation appear to result from
the coordination of the 3-pyridyl group by a palladium ion,
which could influence the configuration of the methyl(3-
pyridylmethyl)amino moiety, causing more effective
donation of a lone pair of electrons from peripheral nitro-
gen to the macrocyclic ring.
Experimental
All reactions were conducted in oven-dried glassware under
nitrogen. Reaction temperatures reported refer to external
bath temperatures. Methanol and dichloromethane were
distilled. Other solvents and all reagents were obtained from
commercial suppliers and used without further purification.
Melting points were obtained on a ‘‘Stuart’’ Bibby Sterlin
Ltd.Ò melting point apparatus. All solvents were evaporated
at or below 50 °C. Chromatography was carried out on
Merck silica (eluents are given in parentheses). Dry flash
column chromatography was carried out on silica gel 60,
particle size 40–63 lm. Thin-layer chromatography (TLC)
123

Experimental and computational study on the reactivity of amino substituents
605
Fig. 4 Tribenzoporphyrazine 8
(black line) titrated with
PdCl2(PhCN)2 in
dichloromethane:methanol
(1:1). Variations of the Q-band
in different solvents (inset)
Table 2 Variations of the
Q-bands for 8 and 9 in different
solvents
Solvent
Dipole
moment (l)
Refractive
index (nD)
Q-band
(kmax, nm) 8
Q-band
(kmax, nm) 9
Acetonitrile
Ethyl acetate
Methanol
THF
3.92
1.78
1.70
1.75
0.37
1.60
2.21
1.344
1.372
1.328
1.407
1.497
1.455
1.510
723
726
727
728
728
731
736
661, 733
730, 799
662, 736
658, 732
741, 803
760, 807
666, 742
Toluene
Dichloromethane
Pyridine
was performed on silica gel Merck Kieselgel 60 and 60 F254
plates. UV–Vis spectra were recorded on a Hitachi UV/VIS
U-1900 spectrometer. 1H and 13C NMR spectra were
recorded on Varian Unity 300 FT and Bruker DRX-400
spectrometers. Chemical shifts (d) are quoted in parts per
million (ppm) and are referred to a residual solvent peak.
Coupling constants (J) are quoted in Hertz (Hz) to the
nearest 0.5 Hz. The abbreviations s, d, t, p, m, and Ar refer
to singlet, doublet, triplet, pentet, multiplet, and aromatic,
respectively. Additional techniques [1H-1H correlation
spectroscopy (COSY), heteronuclear multiple quantum
coherence (HMQC), heteronuclear multiple bond coher-
ence (HMBC)] were used to assist allocation. Analytical
high-performance liquid chromatography (HPLC) was
performed on an Agilent 1200 instrument using Agilent
Eclipse XDB-C18 (150 9 4.6 mm, 5 lm) column. Low-
and high-resolution mass spectrometry [chemical ionization
(CI), electrospray ionization (ESI), matrix-assisted laser
desorption/ionization (MALDI) time of flight (TOF)] were
recorded by both the Imperial College London Department
of Chemistry Mass Spectrometry Service and the Advanced
Chemical Equipment and Instrumentation Facility at the
Faculty of Chemistry, Adam Mickiewicz University in
Poznan. Elemental analyses were determined by the
Advanced Chemical Equipment and Instrumentation
Facility at the Faculty of Chemistry, Adam Mickiewicz
University in Poznan.
Crystallography
Single crystals of 4 and 5 were obtained at room temper-
ature from ethyl acetate:n-hexane solution. A summary of
structure determination is given in Table 3. Intensity data
were collected with a Kuma Diffraction KM4-CCD dif-
fractometer using graphite-monochromated Mo Ka
radiation. All structures were solved by direct methods
with SHELXS97 and were refined with SHELXL97 by
full-matrix least-squares based on F2 [24]. All non-hydro-
gen atoms were refined anisotropically. Hydrogens at
amine N atoms were located on an electron density
123

606
T. Goslinski et al.
2-[(3-Pyridylmethyl)amino]-3-[(3-pyridylmethylidene)-
amino]-2(Z)-butene-1,4-dinitrile (4, C16H12N6)
Table 3 X-ray experimental details of 4 and 5
4
5
Two drops of CF3COOH were added to 3.0 g 3 (15.1
mmol) and 2.4 g 3-pyridinecarboxaldehyde (22.6 mmol)
dissolved in 60 cm3 methanol. The mixture was stirred for
72 h. Precipitated solid was collected by vacuum filtration
and washed with methanol and diethyl ether to give 2.6 g 4
as a yellow solid (60%). Recrystallization from ethyl
acetate:n-hexane afforded 1.42 g yellow crystals (33%).
M.p.: 206–208 °C; 1H NMR (300 MHz, DMSO-d6):
Formula
C16H12N6
288.32
Monoclinic
P21/n
C16H14N6
290.33
Monoclinic
P21/n
FW
Crystal system
Space group
˚
a (A)
12.0756(4)
7.4357(3)
16.1624(6)
101.664(3)
1,421.26(9)
4
11.963(1)
7.7716(8)
16.241(2)
103.31(1)
1,469.5(3)
4
˚
b (A)
˚
c (A)
4
d = 9.19 (d, J = 1.5 Hz, 1H, pyridine-H), 8.82 (bs, 1H,
b (deg)
NH), 8.65 (dd, 1H, 3J = 5.0 Hz, 4J = 2.0 Hz, pyridine-H),
8.59 (d, 1H, 4J = 2.0 Hz, pyridine-H), 8.53 (dd, 1H,
3J = 5.0 Hz, 4J = 1.5 Hz, pyridine-H), 8.41 (d, 1H,
3J = 8.0 Hz, pyridine-H), 8.37 (s, 1H, N = CH), 7.79
3
V (A )
˚
Z
T (K)
Dc (g/cm3)
l (cm-1
130(2)
140(2)
1.312
1.347
3
4
(dt, 1H, J = 8.0 Hz, J = 2.0 Hz, pyridine-H), 7.50 (dd,
)
0.087
0.084
3
3
1H, J = 8.0 Hz, J = 5.0 Hz, pyridine-H), 7.43 (dd, 1H,
3J = 8.0 Hz, 3J = 4.5 Hz, pyridine-H), 4.68 (d, 2H,
3J = 3.5 Hz, CH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 153.4, 151.8, 150.4, 148.8, 148.7, 135.6, 135.1, 133.8,
131.1, 128.7, 123.8, 123.8, 113.4, 113.0, 103.3, 46.9
(CH2) ppm; MS (CI, NH3): m/z = 289 (M?H?); HRMS
calcd for C16H13N6 289.1202, found 289.1205.
Hmax (deg)
26.4
26.4
R1 (obs. data)
wR2 (obs. data)
Independ. refs.
Refs. I [ 2r(I)
0.035
0.034
0.094
0.085
2,890
2,998
2,199
2,389
2,3-Bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile
(5, C16H14N6)
difference map and refined isotropically. The other H
atoms were generated geometrically, with C–H = 0.93–
˚
0.98 A, and refined as riding on their carriers, with
To 3.33 g 4 (11.5 mmol) suspended in 110 cm3 methanol,
520 mg NaBH4 (13.9 mmol) was added in three portions and
stirred. After the addition was complete, the mixture was
stirred for another 30 min and poured into 300 cm3 ice-water
mixture to form a precipitate. Filtration, drying under
vacuum, and chromatography (dichloromethane:methanol,
10:1) afforded 5 as a yellow oil. Recrystallization from ethyl
acetate:hexane afforded 1.50 g yellow crystals (45%). M.p.:
103–106 °C; 1H NMR (300 MHz, DMSO-d6): d = 8.51
U
iso(H) = 1.2Ueq(C). Details on data collection and
refinement, fractional atomic coordinates, anisotropic dis-
placement parameters, and full list of bond lengths and
angles in CIF format have been deposited at the Cambridge
Crystallographic Data Centre. CCDC 783702 for 4 and
CCDC 783703 for 5 contain the crystallographic data for
this paper. Copy of the data can be obtained, free of charge,
via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or
from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK; fax: ?44-1223-
336033; or e-mail: deposit@ccdc.cam.ac.uk.
4
(s, 2H, 2 pyridine-H), 8.49 (hidden d, 2H, J = 2.0 Hz, 2
pyridine-H), 7.68 (dt, 2H, 3J = 8.0 Hz, 4J = 2.0 Hz, 2 pyr-
idine-H), 7.39 (dd, 2H, 3J = 8.0 Hz, 3J = 5.0 Hz, 2
3
pyridine-H), 6.05 (t, 2H, J = 6.0 Hz, 2 NH), 4.30 (d, 4H,
3J = 6.0 Hz, 2 CH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 148.9, 148.6, 135.2, 134.4, 123.6, 115.2, 109.9, 46.5 (2
CH2) ppm; MS (CI, NH3): m/z = 291 (M?H?); HRMS
calcd for C16H15N6 291.1358, found 291.1368.
Quantum mechanical calculations
The conformational study process of 5 and 5-Na is
described in details in the Supplementary Material. The
condensed Fukui functions and condensed softness (see
references in the Supplementary Material) were obtained
from single-point calculations on the optimized disodium
salt structures of 5 (5-Na) with the 6-31G(d,p) basis set,
using restricted B3LYP for neutral systems and unre-
stricted U-B3LYP hybrid functional for the corresponding
cation and anion calculations. B3LYP functional appears to
be reliable in fkꢁ, fkþ, and fk0 indices calculations [25]. All
calculations were performed using the PC GAMESS/Fire-
fly 7.1.E program [26].
2,3-Bis[methyl(3-pyridylmethyl)amino]-2(Z)-butene-1,4-
dinitrile (6, C18H18N6)
To 40 cm3 dimethylformamide at -30 °C, 265 mg NaH
(60% dispersion in mineral oil, 6.6 mmol) was added and
stirred for 30 min. Further 960 mg 5 (3.31 mmol) in 5 cm3
dimethylformamide was added within 30 min and stirred at
-30 °C for 1.5 h. Finally, 0.59 cm3 Me2SO4 (6.95 mmol)
in 2 cm3 dimethylformamide was added within 40 min at
-10 °C. The mixture was stirred for 1.5 h and carefully
poured into 100 cm3 water-crushed ice mixture. The
123

Experimental and computational study on the reactivity of amino substituents
607
aqueous layer was extracted with EtOAc (4 9 150 cm3).
The combined organic layers were washed with NaHCO3
solution and water. Evaporation and chromatography
(dichloromethane:methanol 10:1) afforded 147 mg (13%)
6 as a brown oil. Rf = 0.19 (ethyl acetate:methanol 5:1);
MS (ESI): m/z = 317 (M - H-), 341 (M?Na?).
(m, 12H, 6 CH2CH2F) ppm; 19F NMR (376 MHz, pyridine-
d5): d = -140.99 (m), -141.04 (m), -141.21 (m) ppm; MS
(MALDI): m/z = 1307.592 (M?H?).
[1,4,8,11,15,18,22,25-Octakis(4-fluorobutoxy)phthalocy-
anato]zinc(II) (9, C64H72F8N8O8Zn) was isolated as a side-
product. Rf = 0.32 (dichloromethane:methanol 10:1); UV–
Vis (dichloromethane:methanol 1:1): kmax (log e) = 328
3,6-Bis(4-fluorobutoxy)benzene-1,2-dicarbonitrile
(7, C16H18F2N2O2)
1
(4.86), 663 (4.74), 738 (5.36), 822 (4.23) nm; H NMR
(400 MHz, pyridine-d5): d = 7.83 (s, 8H, H-2, H-3, H-9,
H-10, H-16, H-17, H-23, H-24), 5.08 (t, 16H, 3J = 6.5 Hz, 8
To a well-stirred slurry of 0.808 g 2,3-dicyanohydroquinone
(5.04 mmol) and 0.484 g NaH (60% dispersion in mineral
oil, 10.08 mmol) in 25 cm3 dimethylformamide cooled to
0 °C, 1.562 g 4-bromo-1-fluorobutane (10.08 mmol) was
added after 1.5 h. The solution was heated at 50 °C for 24 h.
The reaction contents were poured into 65 cm3 water, and
the suspension was vigorously stirred. The resulting white-
cream solid was filtered and next suspended in 100 cm3
methanol keeping under reflux. The filtration of the white
solid afforded 1.447 g (92%) 7. M.p.: 179–183 °C;
Rf = 0.82 (tetrahydrofuran:methanol 1:1); UV (methanol):
kmax (log e) = 226 (4.18), 350 (3.51) nm; 1H NMR
(300 MHz, DMSO-d6): d = 7.62 (s, 2H, H-4, H-5), 4.51
(dt, 4H, 2JHF = 47.5 Hz, 3J = 5.5 Hz, 2 CH2F), 4.20 (t, 4H,
3J = 6.0 Hz, 2 CH2O), 1.74–1.85 (m, 8H, 2 CH2CH2) ppm;
13C NMR (75 MHz, DMSO-d6): d = 154.8, 120.6, 113.5,
2
OCH2), 4.62 (dt, 16H, JHF = 47.5 Hz, 3J = 6.0 Hz, 8
CH2F), 2.38 (p, 3J = 7.0 Hz, 16H, 8 OCH2CH2), 2.15 (dp,
16H, 3JHF = 25.5 Hz, 3J = 7.0 Hz, 8 CH2CH2F) ppm; 19
F
NMR (376 MHz, pyridine-d5): d = -139.97 (m) ppm; 13
C
NMR (100 MHz, pyridine-d5): d = 153.24, 151.97, 128.65,
119.43, 84.4 (d, JCF = 163.0 Hz), 72.16, 27.8 (d,
1
3
2JCF = 20.0 Hz), 26.2 (d, JCF = 5.0 Hz) ppm; MS
(MALDI): m/z = 1 297.572 (M?H?).
General procedure for UV–Vis titrations
of tribenzoporphyrazine 8
CH3OH:CH2Cl2 (1:1) solution of known concentration of
porphyrazine 8 was subjected to UV–Vis titrations with
CH3OH:CH2Cl2 (1:1) solutions of varying concentrations
(0, 0.01, 0.1, 0.5, 1 molar equiv.) of PdCl2(C6H5CN)2.
Blank UV–Vis spectra (in the absence of metal salt) were
run for 8 to determine any solvent effect (of which there
were none). Blank UV–Vis spectra (in the absence of
tribenzoporphyrazine 8) were also run for the metal salt to
make sure that there was no significant absorbance in the
window of interest (300–850 nm).
1
102.8, 83.5 (d, JCF = 161.5 Hz), 69.3, 26.4 (d,
2JCF = 19.5 Hz), 24.3 ppm; MS (CI, NH3): m/z = 326
(M?NH4?); HRMS calcd for C16H22N3O2F2 326.1680,
found 326.1683.
1,4,8,11,15,18-Hexakis(4-fluorobutoxy)-22,23-bis[methyl-
(3-pyridylmethyl)amino]tribenzo[b,g,l]porphyrazinato-
zinc(II) (8, C66H72F6N12O6Zn)
To 2 cm3 pentanol 65 mg 6 (0.20 mmol), 414 mg 7
(1.43 mmol), 300 mg Zn(OAc)2 (1.63 mmol), and
0.244 cm3 1,8-diazabicyclo[5.4.0]undec-7-ene (1.63 mmol)
were added and heated under reflux for 23 h. Evaporation and
chromatography (dichloromethane:methanol 25:1–15:1)
afforded 25 mg greyish-blue 8 (9%) as a thin film. Further
purification by means of PTLC afforded 8 mg (3%).
Rf = 0.29 (dichloromethane:methanol 8:1); UV–Vis
(dichloromethane:methanol 1:1): kmax (log e) = 332 (4.24),
730 (4.36) nm; 1H NMR (400 MHz, pyridine-d5): d = 9.06
Acknowledgments This study was supported in part by Polish
Ministry of Science and Higher Education grant no. N405 031
32/2052. T.G. thanks Professor A.G.M. Barrett from Imperial College
London and Professor S. Sobiak from Poznan University of Medical
Sciences for supporting his studies. The authors thank Mrs B.
Kwiatkowska for excellent technical assistance. Z.D. thanks MSc A.
Maruszewski for preparation of input data for computational study.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
4
(d, 2H, J = 2.0 Hz, 2 pyridine-20H), 8.52 (dd, 2H,
4
3J = 4.5 Hz, J = 1.5 Hz, 2 pyridine-60H), 7.89 (dt, 2H,
4
3J = 8.0 Hz, J = 2.0 Hz, 2 pyridine-40H), 7.87 (s, 2H,
References
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3
3J = 8.5 Hz, 2 Ar–H), 7.07 (dd, 2H, J = 8.0, Hz, J =
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