Structure of the dimers arising from one-electron electrochemical reduction of pyridinium salts 3,5-disubstituted with electron-withdrawing groups

Article abstract of DOI:10.1039/b110140b

One-electron electrochemical reduction of the salts 1-benzyl-3,5-bis(methylcarbamoyl)pyridinium bromide 3a and 1-benzyl-3,5-dicarbamoylpyridinium bromide 3b yields mixtures of four isomeric dimers, as shown by HPLC analysis and mass spectrometry. ¹

Full text of DOI:10.1039/b110140b

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Structure of the dimers arising from one-electron electrochemical
reduction of pyridinium salts 3,5-disubstituted with
electron-withdrawing groups
1
Vincenzo Carelli,* Felice Liberatore, Silvano Tortorella, Barbara Di Rienzo and Luigi Scipione
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
Università degli Studi di Roma ‘La Sapienza’, Piazzale Aldo Moro, 5 00185 Rome, Italy
Received (in Cambridge, UK) 6th November 2001, Accepted 7th December 2001
First published as an Advance Article on the web 18th January 2002
One-electron electrochemical reduction of the salts 1-benzyl-3,5-bis(methylcarbamoyl)pyridinium bromide 3a
and 1-benzyl-3,5-dicarbamoylpyridinium bromide 3b yields mixtures of four isomeric dimers, as shown by HPLC
1
13
analysis and mass spectrometry. H and C NMR spectrometry allows us to determine the structures of the mixture
components. In both mixtures, the two most abundant products are identified as 4,4Ј- and 2,4Ј-tetrahydrobipyridines
(
5a, 5b and 6a, 6b, respectively), while minor amounts of a pair of diastereomeric 2,2Ј-linked dimers are also detected
in (7a, 8a and 7b, 8b respectively). Therefore, the NMR studies lead to the conclusion that the structure assignment
of conformers of 5a, made previously for 6a and 7a, is not correct. All the 2,2Ј- and 2,4Ј-linked dimers undergo
photochemical dissociation into two pyridinyl radicals which recombine to yield 4,4Ј-linked dimers.
Introduction
Several papers dealing with studies on the dimerization of
pyridinyl radicals, generated by one-electron reduction of pyr-
idinium salts 3-substituted with electron-withdrawing groups,
1
have been published. For example, dimer formation by electro-
ϩ
ϩ
chemical reduction of coenzymes NAD and NADP and their
2
models has been extensively investigated, and specific work has
been devoted to elucidation of the role of steric and electronic
3
factors in the regio- and stereoselectivity of the dimerization.
On the other hand, there are in the literature few reports on
dimer formation by reduction of pyridinium salts 3,5-disubsti-
4
tuted with electron-withdrawing groups. Mumm et al., by
treatment of the 3,5-bis(ethoxycarbonyl)-1,2,6-trimethylpyr-
idinium salt with sodium amalgam, obtained a product to
which they assigned the structure of the 2,2Ј-linked dimer 1Ј
(
Scheme 1). Dimer 1Ј, upon heating, underwent rearrangement
to a higher-melting 4,4Ј-linked dimer 2 (Scheme 1). Much later,
Huyser and co-workers, from the electrochemical reduction of
5
the same salt, obtained the lower-melting dimer 1, which upon
heating rearranged to dimer 2. NMR analysis confirmed for 2
the structure of a 4,4Ј-linked dimer, but allowed them to correct
the structure of the lower-melting dimer to that of the 2,4Ј-
6
linked structure 1. In a recent paper, Leprêtre et al. reported
that, by one-electron electrochemical reduction of the 1-benzyl-
3
,5-bis(methylcarbamoyl)pyridinium salt 3a (Scheme 2), they
obtained a mixture of three compounds, two of which were
quantitatively transformed into the third, more stable, compon-
ent by irradiation with a xenon lamp. The said authors claimed
that, on the basis of NMR analysis, the structure of 4,4Ј-linked
dimer 5a (Scheme 2) has to be assigned to the stable compound,
and the same structure it also is to be ascribed to the unstable
compounds, which, therefore, have to be considered conformers
of such a structure. These surprising findings prompted us to
carry out a careful investigation of the dimers arising from one-
electron electrochemical reduction of pyridinium salts 3a and
Scheme 1
anaerobic photocatalysed isomerization of 6a,b, 7a,b and 8a,b
into 5a,b was observed.
3
b (Scheme 2). In our hands the reduction of both 3a and 3b
Results and discussion
Electrolysis of pyridinium salt 3a, carried out in the dark, con-
sumed one electron per mole of salt and gave a crude mixture
which displayed an analytical HPLC profile (Fig. 1a, b) showing
yielded, as shown by analytical HPLC, mixtures of four com-
pounds, to which accurate H and C NMR analysis and mass
spectrometry allowed us to assign the dimeric structures 5a, 6a,
1
13
7
a, 8a and 5b, 6b, 7b, 8b, respectively (Scheme 2). Furthermore,
5
42
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b110140b

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13
a
Table 1
C NMR chemical shifts (δ ppm) of 2,2Ј- and 4,4Ј-linked dimers
C2
C3
C4
C5
C6
NCH2
CH3
C᎐O
5a
5b
7a
135.61 d
139.56
57.61 d
107.05 s
107.78 s
104.64 s
38.89 d
4b0.09 d
107.05 s
107.78 s
113.33 s
135.61 d
139.56
144.52 d
56.78 t
58.72 t
59.27 t
25.40 q
—
25.27q
168.31 s
173.48 s
166.23 s
167.38 s
2
9.08 q
a
DMSO-d ; in spectra of compounds 5a and 7a, the aromatic carbon signals are in the regions δ 127.70–128.71 and 126.06–127.45, respectively; in
6
C
b
the spectrum of compound 5b, the aromatic carbon signals are in the region 128.63–130.94. Signals obscured by the aromatic C signals.
Scheme 2
respectively. In detail, five aromatic, two benzyl, two olefinic, six
methyl, one methine and two amide hydrogens were easily
detectable as well as six aromatic, four ring olefinic, two carb-
onyl, one N-benzylic, one methine and two methyl carbons
(
Tables 1 and 3). Furthermore, as regards I, the chemical shift
of methine protons and carbons (δ 4.81 and δ 57.61, respect-
C
ively), clearly indicated their position next to the ring nitrogen
1c,2a
atom
and, therefore, allowed us to certainly identify I as a
2
,2Ј-linked dimer. As regards II, the chemical shifts of methine
protons and carbons (δ 3.82 and δ 38.89, respectively) unam-
C
bigously indicated the positions 4 as the dimer-junction
1c,2,3
sites
and, consequently, permitted us to identify II as a 4,4Ј-
linked dimer. On such results the structures 7a and 5a were
assigned to I and II, respectively (Scheme 2).
1
13
The complexity of the H and C NMR spectra (thirty-six
proton signals and thirty-two carbon peaks) (Tables 2 and 4)
strongly suggested an asymmetric dimeric structure for com-
1
13
pound IV. In fact, by comparison with the H and C spectra
of 5a and 7a, the presence in IV of both 1-benzyl-3,5-bis-
(
methylcarbamoyl)1,2- and -1,4-dihydropyridine moieties was
certainly detected. Significatively, the presence of two methine
hydrogens at δ 4.45 and 4.04 and two methine carbons at δC
Fig. 1 (a) HPLC elution profile of crude mixture obtained from the
reduction of salt 3a. The eluate was monitored at 275 and 380 nm.
6
1.01 and 38.96 clearly indicated the positions 2 and 4 as dimer-
coupling sites, thus showing that IV was a 2,4Ј-linked dimer,
consistent with the structure 6a (Scheme 2).
Retention times (t ) start from injection point. (b) UV spectra were
R
recorded on the top of the corresponding chromatographic peaks and
1
13
Careful H and C NMR analyses, carried out on the iso-
are normalized with respect to their own λmax
.
lated dimers 5a, 6a and 7a, made easier the identification of the
1
fourth, not isolable, component III. The H NMR spectrum of
two main and two secondary peaks, according to the following
sequence: I (tR 46.5 min), II (tR 52 min), III (tR 54 min) and
IV (tR 79.5 min). Separation of components I, II and IV was
performed by preparative HPLC, whereas component III,
owing to its high lability to light, could not be isolated. I, II and
IV were identified by mass spectrometry as dimers formed by
the coupling of the radical 4a (Scheme 2) arising from elec-
trolysis. The symmetric structure of both I and II was clearly
the crude reduction mixture displayed, besides the proton sig-
nals of 7a, a parallel series of eighteen peaks (Table 3), which
was indicative of the same structural pattern, thus confirming
the presence of another 2,2Ј-linked dimer, consistent with the
structure 8a. This structure was also confirmed by the UV
spectrum, quite superposable on that of 7a (Fig. 1b), both
spectra being consistent with the chromophore systems of 3,5-
dicarbamoyl-substituted 1,2-dihydropyridines. Therefore, 7a
and 8a were identified as a pair of diastereomers with respect to
the C2–C2Ј stereochemistry.
7
1
13
shown from the presence in their H and C NMR spectra of
only eighteen proton signals and only sixteen carbon peaks
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547
543

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1
Finally, thorough H NMR analysis of each of the four iso-
meric dimers allowed us to determine the following relative
1
abundances from the H NMR spectrum of the crude reduction
mixture: 5a 53%, 6a 36%, 7a 6%, 8a 5%.
Monitoring by HPLC of the crude reduction mixture
exposed to UV-light (254 nm), under anaerobic conditions,
showed the gradual conversion of 6a, 7a and 8a into 5a: the
transformation of 7a and 8a was complete in a short time,
whereas, after 120 min, just 60% of the isomerization of 6a had
occurred (Fig 2a, b).
Fig. 2 (a) HPLC elution profile of dimer mixture from the reduction
of salt 3a after 120 min of exposure to UV light. The eluate was
monitored at 275 and 380 nm. Retention times (t ) start from injection
R
point. (b) UVspectra were recorded on the top of the corresponding
chromatographic peaks and are normalized with respect to their own λmax
.
As shown in the analytical HPLC elution profile reported in
Fig. 3a, four products were also found in the mixture arising
from the one-electron electrochemical reduction of salt 3b. The
four components were eluted according to the following order I
(
tR 6.5 min), II (tR 9.2 min), III (tR 10.3 min) and IV (tR 11.5
min). Owing to the high lability to light of I and III, only the
major components II and IV were isolated by preparative
1
13
HPLC. Their H and C NMR spectra were completely com-
parable, except for the missing NCH resonances, with the cor-
3
responding spectra of 5a and 6a (Tables 1–4). Therefore, to II
and IV have to be assigned the structures of 4,4Ј-linked dimer
5
b and 2,4Ј-linked dimer 6b, respectively (Scheme 2). The same
parallelism could be observed between the NMR hydrogen
signal sequences and UV spectra of 7a and 8a and those of I
and III (Table 3 and Fig. 3b), which were thus identified as a
pair of diastereomeric 2,2Ј-linked dimers, consistent with the
1
structures 7b and 8b (Scheme 2). Again. the complete H NMR
analysis of each of the four isomeric dimers allowed us to
1
evaluate the following relative abundances from the H NMR
spectrum of the crude reduction mixture: 5b 49%, 6b 40%, 7b
4
.5%, 8b 6.5%.
In this case as well, exposure of the crude reduction mix-
ture to UV-light (254 nm), in the absence of air, produced the
gradual transformation of 6b, 7b and 8b into 5b: both 7b and 8b
were totally converted after few min, whereas, after 100 min,
only a 50% of isomerization of 6b was observed (Fig. 4a, b).
The results reported in this paper show that the dimerization
of both the radicals 4a and 4b gives rise to formation of all four
dimers theoretically possible: in fact, only one compound is to
be expected as regards the 4,4Ј-linked dimers because of their
molecular simmetry, as well as only one compound (a racemate)
for the single asymmetric carbon of the 2,4Ј-linked dimers,
whereas two diastereomers (a racemate and a mesoform) are
consistent with the two equivalent asymmetric carbons of the
2
,2Ј-linked dimers.
5
44
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547

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1
a
Table 3 H NMR chemical shifts (δ ppm) and coupling constants (J Hz) of 2,2Ј-and 4,4Ј-linked dimers
NCH2
a
b
H2
H4
H6
H
H
NH
CH3
NH2
J4,6
J(CH3NH)
Ja,b
5
7
a
a
6.98 s
4.81 s
3.82 s
7.14 d
6.98 s
7.13 d
4.41 s
4.57 d
6.61 m
6.53 m
2.73 d
2.75 d
2.77 d
2c .65 d
or
or
4.49 d
4.87 d
1.45
4.65
5.00
15.40
15.90
6
.29 m
b
8
a
4.74 s
7.16
7.15
4.53 d
5b
7b
8b
6.90 s
4d.74 s
3.96 s
7.10 d
7.09 s
6.90 s
7.07 d
7.06s
4.43 s
4d.51 d
6.74
b
b
or
or
4d.68 d
15.80
a
DMSO-d ; in the spectra of compounds 5a, 7a and 8a, the aromatic proton signals are in the regions δ 7.29–7.47 and δ 7.29–7.50, respectively; in the
6
b
spectra of compounds 5b, 7b and 8b, the aromatic proton signals are in the regions δ 7.23–7.39 and δ 7.20–7.49, respectively. Chemical-shift values
c
d
measured in the spectra of crude reduction mixtures of salts 3a and 3b. Signal obscured by CH signal of compound 5a. Signal obscured by NCH2
3
signal of compound 6b.
Fig. 3 (a) HPLC elution profile of crude mixture obtained from the
reduction of salt 3b. The eluate was monitored at 275 and 380 nm.
Fig. 4 (a) HPLC elution profile of dimer mixture from the reduction
of salt 3b after 100 min of exposure to UV light. The eluate was
Retention times (t ) start from injection point. (b) UV spectra were
R
monitored at 275 and 380 nm. Retention times (t ) start from injection
R
recorded on the top of the corresponding chromatographic peaks and
point. (b) UV spectra were recorded on the top of the corresponding
are normalized with respect to their own λmax
.
chromatographic peaks and are normalized with respect to their own λmax
.
The clear predominance (about 70%), among the reduction
products of salts 3a and 3b, of dimers involving the positions
as ring–ring bond sites, indicates that, also in the case of
Experimental
4
Materials and methods
radicals 4a and 4b, the electron-spin density is far larger located
3b
on carbons 4. Nevertheless, notwithstanding the considerable
steric hindrance about the carbons 2, electron-spin density on
the said carbons is sufficiently large to allow the formation of
substantial amounts of both 2,2Ј- and 2,4Ј-linked dimers.
The anaerobic photo-induced rearrangement of the dimers
Pyridine-3,5-dicarboxylic acid was purchased from Aldrich
Chemical Co. All the other chemical reagents and solvents were
purchased from Fluka Chemie A.G.
Melting points were taken on a Tottoli apparatus and are
uncorrected. UV spectra were recorded on a Perkin-Elmer
Lambda 40 UV/Vis spectrophotometer. The spectrophoto-
metric data were processed using the Perkin-Elmer UV WinLab
6
a, 7a, 8a as well as of 6b, 7b, 8b is consistent with a unimole-
cular homolysis process producing the radicals 4a and 4b,
which rapidly recombine to form the photochemically stable
dimers 5a and 5b. As evident from Figs. 3 and 4, the 2,2Ј-linked
dimers undergo homolysis considerable faster than do 2,4Ј-
linked dimers because of their greater steric crowding in the
region of the bond undergoing cleavage. Similar photocatalysed
1
13
software. H and C NMR spectra were recorded on Bruker
AM-200 and AMX-500 spectrometers; chemical shifts are
given in ppm (δ) from tetramethylsilane as internal standard;
coupling constants (J) are in Hz.
Mass spectral data were obtained on a Waters 2 MD
detector, using positive electrospray ionization mode (ESI ϩ).
Analytical HPLC was carried out with an LC Perkin-Elmer
series 200 apparatus, equipped with Perkin-Elmer 235 C diode
array detector and Merck RP-18 LiChroCART 250–4 7 µm and
Supelco Hypersyl 250–4 7 µm columns. The chromatographic
data were processed using Perkin-Elmer Turbochrom and
Turboscan softwares. Preparative HPLC was carried out with a
LC Perkin-Elmer series 3 apparatus, equipped with an LC 55
UV detector and a Merck RP-18 LiChroCART 250–25 7 µm
column.
ϩ
rearrangements of NAD and other nicotinamide dimers have
1c,8
been already reported. These simple isomerizations indicate
that the carbon–carbon bond coupling the dihydropyridine
moieties is so weak that only a low activation energy is required
for the dimer’s dissociation into pyridinyl radicals. Evidently,
besides the steric factors, the resonance stabilization of the
radicals being formed is the determining factor which allows a
lower activation energy requirement for the homolysis. An
unexpectedly low activation energy was also found for the
5
thermal rearrangement of dimer 1 to 2.
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547
545

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Controlled-potential electrolyses were performed by means
of an Amel mod 555/A potentiostat equipped with an Amel
mod 721 analogic integrator, and a three compartment cell,
3a
according to the procedure reported in a previous paper.
Photocatalysed isomerizations were carried out in vacuum-
sealed vials using a shortwave (254 nm) Spectroline UV lamp,
Ϫ2
mod. EF-140C, one 4 W tube, peak intensity 570 µW cm at
1
5 cm.
N,NЈ-Dimethyl pyridine-3,5-dicarboxamide
Pyridine-3,5-dicarbonyl dichloride (12 g) was added portion-
3
wise to 100 cm of stirred, ice-cooled 40% aq. methylamine. The
precipitated solid was filtered off, and washed with cold water.
Recrystallization from aq. EtOH gave pure N,N Ј-dimethyl
pyridine-3,5-dicarboxamide (9 g, 62%); mp (from aq. EtOH)
9
2
20–222 ЊC (lit., 221–223 ЊC); δH (500 MHz; DMSO-d ) 9.08
6
(
2
2H, d, J 1.9, H2), 8.79 (2H, m, NH), 8.57 (1H, t, J 1.9, H4),
.81 (6H, d, J 3.5, CH ).
3
Pyridine-3,5-dicarboxamide
2 g of pyridine-3,5-dicarbonyl dichloride were added portion-
1
3
wise to 150 cm of stirred, ice-cooled 30% aq. ammonia. The
precipitated solid was filtered off, and washed with cold water.
Recrystallization from aq. EtOH gave pure pyridine 3,5-
dicarboxamide (7.5 g, 77%); mp (from aq. EtOH) 303–305 ЊC
9
(
lit., 303–304 ЊC); δ (500 MHz; DMSO-d ) 9.11 (2H, d, J 1.8,
H
6
a
H2 ϩ H6), 8.64 (1H, t, J 1.8, H4), 8.24 (2H, s, NH ), 7.64 (2H, s,
b
NH ).
Pyridinium salts 3a and 3b
Benzyl bromide was added dropwise to an acetonitrile solution
of the appropriate pyridine derivative. The solution was then
heated under reflux for 16 h. On cooling, the separated solid
was filtered off, and washed successively with cold acetonitrile
and diethyl ether. Recrystallization from EtOH gave in good
yield (85–90%) the expected pyridinium salt.
1
-Benzyl-3,5-bis(methylcarbamoyl)pyridinium bromide 3a.
Mp (from EtOH) 259–260 ЊC; δH (500 MHz; DMSO-d ) 9.66
6
(
2H, d, J 1.56, H2 ϩ H6), 9.30 (1H, t, J 1.56, H4), 9.18 (2H, m,
NH), 7.44–7.59 (5H, m, ArH), 5.96 (2H, s, CH ), 2.87 (6H, d,
2
J 4.62, CH ).
3
1
-Benzyl-3,5-dicarbamoylpyridinium bromide 3b. Mp > 300
ЊC; δH (500 MHz; DMSO-d ) 9.67 (2H, d, J 1.60, H2 ϩ H6),
6
a
b
9
.38 (1H, d, H4), 8.60 (2H, s, NH ), 8.23 (2H, s, NH ),
7
.45–7.63 (5H, m, ArH); 5.97 (2H, s, CH ).
2
Electrochemical reduction of salt 3a
-Benzyl-3,5-bis(methylcarbamoyl)pyridinium bromide 3a
1
3
(
1.3 g) was added to 300 cm of pH 7 0.1 M NaH PO buffer
2 4
and the solution was electrolysed at Ϫ1.0 V vs SCE, under
vigorous stirring and in the dark. After 2 h a faradaic value of
1
± 0.1 was measured, consistent with the uptake of one elec-
tron per mole of pyridinium salt, while the current intensity fell
to the value of the pre-electrolysed buffer solution. The suspen-
3
sion was extracted with three 100 cm portions of dichloro-
methane. The organic solution was washed with water, dried
(
Na SO ), and then evaporated to yield 950 mg of a crude
2 4
residue that was analysed by HPLC with the following solvent
system: MeOH 42%–0.01 M aq. NH HCO 58%; flow rate
4
3
3
Ϫ1
1
cm min . The eluate was monitored at 275 and 380 nm. The
elution profile showed four peaks: I (t 46.5 min, λ 286 and
R
max
4
09 nm), II [t 52 min, λ 261 (sh) and 362 nm], III (t 54 min,
R max R
λmax 285 and 410 nm) and IV (t : 79.5 min, λ
295 and
R
max
3
90 nm) (Fig. 1a, b).
5
46
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547

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1
ϩ
13
1
The following dimer relative abundance was shown by H
NMR spectroscopy performed on crude reduction mixture:
m/z 534.8 (M ϩ Na) ; C NMR (see Table 1), H NMR (see
Table 3).
7
a (I) 6%; 5a (II) 53%; 8a (III) 5%; 6a (IV) 36%.
The second fraction yielded 1,1Ј-dibenzyl-1,1Ј,2,4Ј-tetra-
hydro[2,4Ј]bipyridinyl-3,3Ј,5,5Ј-tetracarboxamide 6b (250 mg,
25% yield with respect to the salt 3b); mp 182 184 ЊC; UV
(MeOH) λmax 295 (ε 14 300) and 388 nm (ε 5250); MS (ESI)
m/z 534.8 (M ϩ Na) ; C NMR (see Table 2), H NMR (see
Table 4).
Preparative HPLC (eluent 3 MeOH 55%–0.07
M aq.
Ϫ1
NH HCO 45%; flow rate 8 cm min ) of the crude residue
4
3
(
950 mg) gave three fractions. Each fraction was evaporated
ϩ
13
1
under vacuum to eliminate the methanol, the aqueous solution
was repeatedly extracted with dichloromethane, and, lastly, the
organic solvent was removed.
The first fraction afforded 1,1Ј-dibenzyl-1,1Ј,2,2Ј-tetrahydro-
N,NЈ,NЉ,NЈ-tetramethyl[2,2Ј]bipyridinyl-3,3Ј,5,5Ј-tetracarbox-
Photocatalysed rearrangement of 2,2Ј-and 2,4Ј-linked dimers to
4,4Ј-linked dimers
amide 7a; mp 164–166 ЊC; UV(MeOH) λ
MS (ESI) m/z 591.2 (M ϩ Na) ; C NMR (see Table 1), H
286 and 409 nm;
max
ϩ
13
1
Samples of the crude mixtures from the reduction of 3a and 3b
were dissolved in CH Cl and exposed to irradiation, at 254 nm,
2
2
NMR (see Table 3).
in vacuum-sealed vials. At appropriate time intervals the com-
position of the solutions was monitored by analytical HPLC:
the chromatograms showed the rapid disappearance of the 2,2Ј-
linked dimers, the gradual decrease of the 2,4Ј-linked dimers,
and the corresponding increase of the 4,4Ј-linked dimers (Figs.
2a, b; 4a, b). Dimers 7a,b and 8a,b totally disappeared in 10–15
min whereas the complete transformation of dimers 6a,b into
1
,1Ј-Dibenzyl-1,1Ј,4,4Ј-tetrahydro-N,NЈ,NЉ,NЈ-tetramethyl-
4,4Ј]bipyridinyl-3,3Ј,5,5Ј-tetracarboxamide 5a (400 mg, 40%
yield with respect to the salt 3a) was obtained from the second
[
fraction; mp (from AcOEt) 189–191 ЊC; UV(MeOH) λ
261
C
max
ϩ
13
sh and 362 (ε 6990) nm; MS (ESI) m/z 591.2 (M ϩ Na) ;
1
NMR (see Table 1), H NMR (see Table 3).
The third fraction yielded 1,1Ј-dibenzyl-1,1Ј,2,4Ј-tetrahydro-
N,NЈ,NЉ,NЈ-tetramethyl[2,4Ј]bipyridinyl-3,3Ј,5,5Ј-tetracarbox-
amide 6a (270 mg, 27% yield with respect to the salt 3a); mp
5
a,b was observed after 160–180 min.
(
from AcOEt) 176 178 ЊC; UV (MeOH) λmax 295 nm (ε 14 600)
ϩ 13
Acknowledgements
and 390 (ε 5336); MS (ESI) m/z 591.2 (M ϩ Na) ; C NMR
1
(
see Table 2), H NMR (see Table 4).
This work was supported by 60% funding from MURST
(
Italy).
Electrochemical reduction of salt 3b
-Benzyl-3,5-dicarbamoylpyridinium bromide 3b (1.3 g) was
1
3
References
added to 300 cm of pH 7 0.1 M NaH PO buffer, and the
2
4
solution was electrolysed, in the dark, at Ϫ1.0V vs SCE under
the above reported conditions. At the end of the electrolysis the
solution was lyophilized, in a dark-glass flask, to a dry residue,
which was extracted with MeOH. Removal of the solvent
yielded a crude product (900 mg), which was analysed by HPLC
using the following solvent system: MeOH 55%–0.01 M
1 (a) P. J. Elving, in Topics in Bioelectrochemistry and Bioenergetics,
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Bull. Chem. Soc. Jpn., 1979, 52, 2674; (d ) J. Kovar and H. Klukanova,
Biochim. Biophy. Acta, 1984, 788, 98.
(a) V. Carelli, F. Liberatore, A. Casini, R. Mondelli, A. Arnone,
I. Carelli, G. Rotilio and I. Mavelli, Bioorg. Chem., 1980, 9, 342; (b)
E. Ragg, L. Scaglioni, R. Mondelli, V. Carelli, I. Carelli, A. Casini,
A. Finazzi-Agro’, F. Liberatore and S. Tortorella, Biochim. Biophys.
Acta, 1991, 1076, 37; (c) F. Micheletti Moracci, F. Liberatore, V.
Carelli, A. Arnone, I. Carelli and M. E. Cardinali, J. Org. Chem.,
2
3
Ϫ1
aq. NH HCO 45%; flow rate 1 cm min . The eluate was
4
3
monitored at 275 and 380 nm.
The elution profile showed four peaks: I (t 6.5 min, λ 288
R
max
and 402 nm), II (tR 9.2 min, λmax 262 and 369 nm), III (tR
1
978, 43, 3420.
1
0.3 min, λmax 288 and 402 nm) and IV (t 11.5 min, λ 295
R max
3
4
5
(a) V. Carelli, F. Liberatore, A. Casini, B. Di Rienzo, S. Tortorella and
L. Scipione, New J. Chem., 1996, 20, 125; (b) V. Carelli, F. Liberatore,
A. Casini, S. Tortorella, L. Scipione and B. Di Rienzo, New. J. Chem.,
1998, 22, 999.
and 388 nm) (Fig. 3a, b).
The following dimer relative abundance was shown by H
NMR spectroscopy performed on the crude reduction mixture:
1
(a) O. Mumm and W. Beth, Ber. Dtsch. Chem. Ges., 1921, 54, 1591;
7
b (I) 4.5%; 5b (II) 49%; 8b (III) 6.5%; 6b (IV) 40%.
(
(
b) O. Mumm and H. Ludwig, Ber. Dtsch. Chem. Ges., 1926, 59, 1605;
c) O. Mumm and J. Diederichsen, Justus. Liebigs Ann. Chem., 1939,
Preparative HPLC (eluent MeOH 45%–0.07 M aq. NH -
4
3
Ϫ1
HCO 55%; flow 7 cm min ) of the crude residue (900 mg)
3
5
38, 195.
gave two fractions. Each fraction was evaporated under vacuum
to eliminate the methanol, the aqueous solution was repeatedly
extracted with dichloromethane, and the organic solvent
removed to dryness.
F. T. McNamara, J. W. Nieft, J. F. Ambrose and E. S. Huyser, J. Org.
Chem., 1977, 42, 988.
6 J. C. Leprêtre, D. Limosin, G. Pierre, P. Chautemps and J. L. Pierre,
Eur. J. Org. Chem., 1998, 2237.
7
K. Wallenfels and H. Schuly, Justus Liebigs Ann. Chem., 1959, 621,
1
,1Ј-Dibenzyl-1,1Ј,4,4Ј-tetrahydro-[4,4Ј]bipyridinyl-3,3Ј,5,5Ј-
tetracarboxamide 5b (350 mg, 35% yield with respect to the salt
b) was obtained from the first fraction, mp 194–196 ЊC; UV
MeOH) λmax 262 (ε 13 950) and 369 nm (ε 7150); MS (ESI)
1
06.
8
L. Avigliano, V. Carelli, A. Casini, A. Finazzi-Agro’ and F.
Liberatore, Biochim. Biophys. Acta, 1983, 723, 372.
3
(
9 H. Meyer and H. Tropsch, Monatsch. Chem., 1914, 35, 781.
J. Chem. Soc., Perkin Trans. 1, 2002, 542–547
547