Genera l Papers ARKIVOC 200 9 (xiii) 342 -362 [618469]

Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
Wurster aza-crown ethers with
N-para- phenylene-phenothiazine or -phenoxazine groups

Ana Cristina Radutiu,a Ion Baciu,b Miron T. Caproiu,c Constantin Dr aghici,c
Adrian Beteringhe,a Gabriela Ion ita,a Petre Io nita,a,b Tant a Spataru,a Nicolae Spataru,a
Rodica D. Baratoiu,a Titus Contantinescu,a and Alexandru T. Balaband*

a Roumanian Academy, “Ilie Murgulescu” Institute of Physical Chemistry, Splaiul Independentei
202, 060021, Roumania
b University of Bucharest, Department of Organic Chemistry, Soseaua Panduri 90-92,
Bucharest, Roumania
c Roumanian Academy, “C. D. Nenitzescu” Instit ute of Organic Chemistry, NMR Department,
Splaiul Independentei 202 B, Bucharest, Roumania
d Texas A&M University at Galveston, 5007 Ave. U, Galveston, TX, 77553-1675, USA
E-mail: [anonimizat]

Abstract
N-Phenylaza-15-crown-5 3 reacts with phenothiazine 1a, 2-chlorophenothiazine 1b, or
phenoxazine 1c in the p resence of m ild oxidizing agents (I 2, Fe3+ or Cu2+) affording new W urster
aza-crown-ethers 4a–4c. Hom olytic processes for the form ation of com pounds 4a-4c were
discussed. Redox properties of these com pounds we re investigated by cyclic voltammetry. In
concentrated sulfuric acid as solvent and oxidant , these com pounds give stable radical-cations as
proved by electron param agnetic resonance (EPR ). Ionophoric properties of the new com pounds
4a-4c were evidenced by cyclic v oltamm etry with lith ium and sodium cations. The relative
hydrophobic/hydrophilic character of these com pounds was determ ined by reverse-phase thin-
layer chromatography (RP-TLC). Redox and ionophoric properties of the new compounds 4a–4c
may lead to analytical an d bioanalytical applications.

Keyw ords: Phenothiazine, phenoxazine, Wurster’s cro wn analogs , cyclic v oltamm etry,
spectrophotom etry, EPR, RP-TLC

Introduction

“Wurster’s Blue” ( N,N,N',N'-tetramethyl-1,4-benzenediam ine ra dical-cation) was described in
1879.1-3A spectacu lar reaction is sho wn on the web, and tak es place b etween a co lorless solu tion
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
of tetram ethyl para -phenylenediam ine on treatm ent with brom ine gas affording a deep blue
solution that becom es colorless aga in with an ex cess of brom ine due to the sequentia l formation
of the radical-cation and the dication.4 “Wurster’s aza-crown-ethers ” that have been describ ed so
far exhibit interesting chrom ophor ic, ionophoric and redox prope rties, but their synthesis
involves several steps.5-17
Derivatives of phenothiazine 1a and 2-chlorophenothiazine 1b have rem arkable biological
activities and medical applications,2,18 e. g.: Chlorproethazine, Chlorprom azine,
Levom eprom azine, Methophenazine, Methia zinic acid, Piperacetazine, etc. For 1a derivatives
one can also m ention dyestuffs 2 such as Methylene Blue, Azur A, B and C. Among analogous
phenoxazine 1c derivatives with various uses,19 one can mention natural antibiotics such as
actinom icines, dyes such as Meld ola`s Blue and gallocy anine, and reagents for analytical o r
bioanaly tical uses such as Am plex Red Reagent (10 -acety l-3,5-d ihydroxy-phenoxazine),
Resorufine (7-hydroxyphenoxazine-3-one- N-oxide) and its sodium salt as well as 6-chloro-9-
nitro-5-oxo-5 H-benzo[ a]phenoxazine.19,20
Till now, no “ Wurster’s crowns” coupled with heterocycles 1a, 1b or 1c have been
describ ed. We present here a s traightforwar d pathway for obtainin g “W urster’s aza-crown –
ethers ” 4, involving a simple homolytic aromatic substitution of N-phenylaza-15-crown-5 3 by a
free radical 2 resulting f rom 1a, 1b or 1c (Schem es 1 and 2).

XN
XN
XN
XNH H+
….
..
.. .._
H_.1a-1c
2a-2cXNH+.._
XN…R R R
R R R

Scheme 1. A few of the resonan ce st ructures of phenothiazines 1a, 1b and phenoxazine 1c and
of the corresponding neutral free radicals 2a–2c : a, X=S, R= H; b, X=S, R=Cl; c, X=O, R=H.

The yield in the “W urster’s aza-crown-ethers ” 4a–4c is satisfactory (above 50%) for this
direct synthetic approach (Schem e 2). The pr esent communication describes the synthesis and
properties o f these new “W urster’s aza-crown-ethers ” 4, com bining the ionophoric affinity for
Li+ and Na+ with the chrom ophoric and redox pr operties of the W urster m oiety.8,9

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XNO O
O
NO
RNO O
O O
+._H
2a-2c
3 4a-4c

Scheme 2. One-step sy nthesis of Wurster aza-crown-ethers 4: homolytic aromatic su bstitu tion of
N-phenylaza-15-crown-5 3 by free radicals 2a–2c (with a, R=H, X=S; b, R=Cl, X=S; c, R=H,
X=O) resulting from the oxidation of phe nothiazine or phenoxazine derivatives.

Results and Discussion

Synthesis of compounds 4a–4c. Reac tion cond itions and mechanism
Oxidation of the three heterocy cles3,18,19 1a–1c converts them into f ree radicals 2a–2c , as seen in
Schem e 1, which dim erize rapidly to 5 and 618,19,21,22 (with an N–C bond).

7IO
O
ONO.
XNHXNH
X
N
XN RR
RR
5a-5c 6a-6c
a, X=S, R=H; b, X=S, R=Cl ; c, X=O, R=H.

Some oxidative reactions of phenothiazine 1a and phenoxazine 1c involve hetero lytic reactions
in the presence of nucleophiles and afford colo red products with quinonoid structures (by
substitution of the heterocyclic ring), whic h can be reduced to the corresponding leuco-
derivatives.23-25 In the present case, however, the react ion mechanism in m ethanol at room
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
temperature in th e presence of m ild oxidizing ag ents (I 2, Fe3+ or Cu2+) is a homolytic aromatic
substitution , involving the N-phenylaza-15 -crow n-5 3 and the nitrogen atom of the free radicals
2a–2c (Schem e 1), affording com pounds 4a–4c (Schem e 2). This s tatem ent is based on th e
following experim ental observations:
i. as seen in T able 1 for the first oxidation step, compounds 1a–1c are oxid ized m ore easily
than N-phenylaza-15-crown-5 3;
ii. irrespective of the oxidizing agent (I 2, Fe3+ or Cu2+), the dim ers 5a, 5c and 6a, 6c
(evidenced by TLC, along with other side-produ cts), proved the form ation of the neutral
free radicals 2a–2c ;
iii. since the literatu re mentions that d imers 5a and 6a are for med from phenothiaz ine 1a and
the stable free radical DPPH (2,2-di phenyl-1-picrylhydrazyl) or solid PbO 2,3,26,27 we
investigated the reactio n between 1a and 3 in m ethylene chlorid e and each of thes e two
oxidizing agents at room tem perature for 24 hrs; along with dim ers 5a and 6a in signif icant
amounts, TLC showed the presence of 4a in low concentr ation ;
iv. on m onitoring by cyclic voltamm etry the reaction of 1a with 3 in acetonitrile, one
reversible m ajor peak was detected (F igure 1), and T LC of the oxidation products
evidenced the electroch emical for mation of 1a, 3, 4a and dim ers 5a and 6a in the absence
of che mical oxidants (see Experim ental Part);
v. no reaction occurs when phenothiazine 1a is replaced by N-m ethylphenothiazine; this
experim ent proves that the N- centered stab le free rad ical 2a is essential for the form ation of
4a;
vi. sodium acetate, which favors hetero lytic pro cesses,24 lowers the yield in products 4a or 4c,
as one can see in Table 2 (the ratios between th e arom atic hetero cycle, 1a or 1c, N-
phenylaza-15-crown-5 3 and oxidizing agent are also displayed in Table 2).

Table 1. Peak potentials (V vs. Ag/ Ag+) for oxi dation (Epa I and EpaII) and reductio n (EpcI and
EpcII) of com pounds 1a–1c and 3 (10-3M) in ace tonitr ile in the pr esenc e of tetra- n-
butylamm onium perchlorate, TBAP (10-1M)
Com pound EpaI EpcI EpaII EpcII
1a 0.30 0.18 0.71 –
1b 0.41 0.31 0.71 –
1c 0.36 0.22 0.85 –
3 0.50 – – –

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Figure 1. Cyclic vo ltammogram recorded for a m ixture of 1a and 3 in aceton itrile with TBAP
(10-1M) as supporting electrolyte in concentrations of 10-3 M, at a scan rate of 0.5 V/s; Epa=0.27
V and Epc=0.16V.

Table 2. Yields of compounds 4a, 4c as a function of experim ental conditions a
%b relative to 1a, 1c Reactants (molar ratio) CH 3COONa (moles
relative to 1a, 1c) 4a 4c
1a+3+I2 (1:1:1) 29
1a+3+I2 (1:1:1.5) 52
1a+3+I2 (1:1:2.2) 48
1a+3+I2 (1:1:1) 2.2 17
1a+3+I2 (1:1:1.5) 2.2 33
1a+3+I2 (1:1:2.2) 2.2 25
1a+3+ FeCl 3 anh. (1:1:1.5) 31
1a+3+FeCl 3 anh. (1:1:1.5) 2.2 26
1a+3+FeCl 3.6H 2O (1:1:1.5) 24
1a+3+FeCl 3.6H 2O (1:1:1.5) 2.2 22
1a+3+CuCl 2.2H 2O (1:1:1.5) 50
1a+3+CuCl 2.2H 2O (1:1:1.5) 2.2 32
1c+3+I2 (1:1:1.5) 51
1c+3+I2 (1:1:1.5) 2.2 23
1c+3+FeCl 3 anh. (1:1:1.5) 30
1c+3+FeCl 3 anh. (1:1:1.5) 2.2 10
a solvent m ethanol at room tem perature for 24 hrs under stirring;
b after work-up and isolation by TLC (see Experim ental Part).

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When iodine was used as an oxid izing agent fo r the reactio n between 1a-1c and 3, another
product ( 7 in 10-15% yield relatively to 3) was identified, in addition to 4a–4c , 5a–5c , and 6a–
6c. The iodo-derivative 7 has been described in the literat ure as the reaction product between 3
and N-iodosuccinim ide, involving proba bly also a hom olytic process.28 We have obtained it as
the m ain reaction product from 3 and iodine in methanol (74% yield, see Experim ental Part).
An excess of oxidizing agent (iodine) up to 50% increases the yield in com pounds 4 but a
large r exces s lowers it ( the first six experim ents in Table 2), so that the other experim ents were
carried ou t with equ imolar am ounts of reactants 1a, 1c and 3, and with 1.5 m oles of oxidant per
mole of each reactant (Table 2).
When iodin e was used as oxidan t, about half of the unreacted crow n ether 3 could be
recove red (2 0%).
The reaction involving 2-chlorophenothiazine 1b with m olar ratios 1b:3:I2 = 1:1:1.5 yielded
the product 4b in 53% yield, indicating that substituted derivati ves of these arom atic
hetero cycles can also b e used satisfactorily.
In the presence of water (or hydrated oxidi zing agents, Table 2) one obtains from 1a or 1c,
along with other side-products, phenothiazin-3-one or phenoxazin- 3-one (these products m ay
also be observed when the first step of the work-up involves aqueous solutions18,19).
Owing to th e basicity of the te rtiary am inic groups, com pounds 4a–4c can be protonated to
4Ha–4Hc in acidic m edia (Schem e 3). The in itial m ixture of the two reac tants N-phenylaza-15-
crown-5 ( 3) and the aro matic hetero cycle 1a–1c in m ethanol is yellow, but on adding an excess
of oxidizing agent the m ixture becom es deeply colored. Com pounds 4a–4c can be oxidized to
cation -radicals 8a–8c (“Wurster’s aza-crown-ethers”) and dication s 9a–9c, sim ilarly to
“Wurster’s Blue” cation -radical ( N,N,N',N'-tetram ethyl-1,4-benzenediam ine radical-cation4,18,19),
see the Redox reactions para graph. In acid and oxidative medium , dication-radicals 8Ha–8Hc
and dications 9a–9c may also be form ed (Sche me 3), s ee EPR spectra paragraph. On adding
reducing agents to this reaction m ixture (ascorbic acid for Fe3+ or Cu2+, or ascorbic acid an d
sodium thiosulf ate f or I2), the color returns gradually to yellow, reform ing com pounds 4a–4c
(see Experim ental Part).
Two less lik ely alternatives to the homolytic aromatic subs titution mechanism presented in
Schem e 2 are: (i) a coupling of two radi cals form ed by oxi dation of both reactants 1 and 3 (as
seen from Table 1, whereas 1a–1c have oxidation potentials of 0.3–0.4 V, the m acrocyclic am ine
3 has a higher oxidation potential, 0.5 V); (ii) a homolytic ipso-substitu tion29 for the case when
iodine was the oxidizing agent, involv ing the form ation of the iodo-derivative 7 that would react
with radical 2a–2c displacing the io dine; actually, on react ing in m ethanol for 24 hrs. at room
temperature an equim olar m ixture of 1a and 7 with an ex cess of anh ydrous FeCl 3 and then
extracting the m ixture with m ethylene ch loride and analyzing th e products by TLC, 4a was
detected in 40% yield.

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XNO O
O
NO..
..
XNO O
O
NO..
XNO O
O
H
NO
..
XNO O
O
H
NO-e-
+e-.+
8a-8c 4a-4c
+
4Ha-4HcR R
R R.++
8Ha-8Hc-e-
+e–H++H+-H++H+
a, X=S, R=H; b, X=S, R=Cl; c, X=O, R= H.XNNO O
O O
R+
+
9a-9c-e-
+e+
-H.+H.

Scheme 3. Reversible processes converting com pounds 4a–4c into conjugate acids 4Ha–4Hc,
and redox processes af fording radical-cations 8a–8c or their conjugate acids 8Ha–48c, and
dications 9a–9c.

NMR and IR Spectra of the new Wurster aza-crow n-ethers 4a-4c
Both by 1H-NMR and 13C-NMR spectra (see Experim ental Pa rt), the struc tures of the new
compounds 4a–4c were confirm ed. The following rem arks should be noted:
i. the symm etry of the unsubstituted hetero cycle 4a and 4c is ref lected by the p airwis e
equality of δ values for H-1-9, H-2- 8, H-3-7, H-4-6 and f or C-1-9, C -2-8, C-3-7, C-4-6;
however, this symmetry is broken by the 2-ch loro-substituen t in 4b;
ii. 1H- and 13C-NMR chemical sh ift δ values f or position s 4 and 6 decrea se on replac ing the
sulfur heteroatom by the more el ectro negativ e oxygen heteroatom 4a>4c;
iii. for com pound 7, NMR data a re similar to those reported in the litera ture28 and confirm the
para -position of the iodo substi tuent in N-phenylaza-15-crown-5, 3.
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
Infrared absorption spectra of com pounds 4a–4c confirm the absence o f the NH stretching
frequency in these products.

Redox reactions of the new Wurster az a-crown-ethers 4a–4c
Cyclic voltammetry of c ompounds 4a–4c using tetra-n-butylammonium perchlo rate (TBAP) as
supporting electroly te evidenced tw o redox reactions (p eaks I and II) in revers ible processes
(Figure 2), corresponding to Schem e 3, similarly to other W urster com pounds.3,5-9

Figure 2. Cyclic voltammogra ms recorded for a concentration of 10-3 M in acetonitrile of
compounds 4a (full lin e, 1), 4b (dotted line, 3 ) and 4c (dashed line, 2); scan rate 0.5 V s-1,
supporting electrolyte T BAP (10-1M).

The oxidatio n potentials (Figure 2 ) increas e in the order 4a<4b≈4c, for each of the oxidation
steps (Tab le 3).

Table 3. Peak potentials (V vs. Ag/ Ag+) for oxi dation (Epa I and EpaII) and reductio n (EpcI and
EpcII) of com pounds 4a-4c (10-3M) in ace tonitrile in th e presenc e of tetra -n-butylammoniu m
perchlorate, TBAP (10-1M)
Com pound EpaI EpcI EpaII EpcII
4a 0.25 0.18 0.68 0.60
4b 0.36 0.27 0.72 0.64
4c 0.35 0.25 0.72 0.62

When Li ClO4 or NaClO 4 are used as a support electrolyt e, the voltammogram s indicated also
a reversible system (Figure 3).

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Figure 3. Characteristic voltamm etric pattern s for 4a (10-3M in ace tonitrile) in the presenc e of
different supporting electrolytes : TMAP (full line, 1), NaClO 4 (dashed line, 2), LiClO 4 (dotted
line, 3); concentration of the supporting electrolyte is 10-1M; scan rate 0.5 V s-1.

With tetramethylamm onium perchlorate (TMAP) as referen ce, Table 4 indicates that th e
oxidation potentials decreas e with these catio ns (Li+ or Na+). This f act proves that the lon e
electron pair of the nitrogen atom in the m acroc ycle becom es involved in the com plex for mation.

Table 4. Oxidation (E paI and EpaII) and red uction (Epc I and EpcII) peak pote ntials (V vs.
Ag/Ag+) of 4a in ace tonitrile (10-3M) in the presence of various supporting electrolytes (10-1M)
Electrolyte EpaI EpcI EpaII EpcII
TMAP 0.26 0.17 0.68 0.60
NaClO 4 0.23 0.11 0.58 0.47
LiClO 4 0.22 0.08 0.58 0.44

Cyclic voltammogra ms (Figure 3) and peak pot entials (Table 4) demonstrated that th e
resulting supram olecular ass embly (4a-M+complex) is stable, and so is also its m ono-oxidation
product ( 8a-M+complex); however, the next oxidation step no longer has a lone electron pair at
the m acrocyclic nitrogen atom , and th erefore this is no longer stable,8,9 but form s the dication 9a
releasing the alkaline m etal cation (S chem e 4).

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SNO O
O
NO
4a..
..
SNO O
O O
N..
..MM+
M+
4a-M+ (comp lex)SNO O
O O
N..MM+
-e- .+
8a-M+ (complex)SNNO O
O O
+
+
9ae- +M++-e-
e-

Scheme 4. Reversible redox ionophoric process of 4a in the presence of alkali m etal ions (M+=Li
or Na)

The com plexation of Li+ or Na+ with 4a (Table 4) is in ag reement with data r eported in the
literature,30 regard ing th e fitting be tween the io nic diam eter and the m acrocyc lic ca vity siz e (1.2-
1.5 Å) of the N-phenylaza-15-crown-5 3 and the ionic diam eters for Li+ (1.36 Å) and Na+ (1.94
Å) respectively. In the case of K+ with larger ionic diameter (2.66 Å),30 our investig ation s
revealed no com plex for mation.

Spectrophotometry of the new Wurster az a-crown-ethers 4a–4c
The electronic absorp tion spectra in the 230-325 nm range of m ethanol solutions of 1a–1c , 3 and
4a–4c are displayed in Table 5. The following observations hold:
i. all seven compounds present two distinct absorption m axima at 238-259 nm and 302-323
nm. In addition, com pounds 4a–4c have a third band at 265nm appearing as a shoulder for
4a and 4b (on the 257 nm or 259 nm absorption band, respectively), but as distinct
maximum for 4c;
ii. taking into account that com pounds 4a–4c possess both m olecular m oieties of 1a–1c and 3,
one expects the presen ce of electronic transi tions characterizing th ese moieties, and in
addition a band that would be sim ilar to that of para -phenylenediam ine;
iii. in solution and as TLC spots, com pounds 1a–1c and the new W urster aza -crown-e thers 4a–
4c are weakly fluorescent at 366 nm ; at presen t, this property was not investigated m ore
closely.

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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
Table 5. Spectrophotometric behavior of com pounds 1, 3 and 4 in m ethanol
Com pounds λ1 max (nm)(logε) λ2 max (nm)(logε) λ3 max (nm)(logε)
1aa252 (4.515) 318 (3.620)
1bb256 (5.023) 323 (4.025)
1cb238 (5.282) 317 (4.593)
3b257 (5.174) 302 (4.330)
4ac257 (4.651) 265 (sh) 312 (3.716)
4bb259 (5.083) 265 (sh) 313 (4.082)
4cb239 (4.733) 265 (4.206) 322 (4.012)
aconcentration 10-4M; bconcentration 10-5M; cconcentration 5×10-5M.

EPR Spectra of radica ls formed from the new Wurster aza-crow n-ethers 4a –4c
In concentrated sulfuric acid as solvent and oxidant, com pounds 4a–4c give stable radicals, but
the reso lution of the EPR spectra is low due to high viscosity of the solvent (F igure 4). We
assum e that under these c onditions, in agreem ent wi th Schem e 3, radicals 8Ha–8Hc becom e
protonated affording radical-dications 8Ha-8Hc .

10 G

8Ha (experim ental) 10 G
8Hb (experim ental) 8Hc (exp erimental)
10 G

8Ha (sim ulated) 10 G
8Hb (sim ulated) 10 G
8Hc (simulated)
Figure 4. EPR spectra of stable radical-dications 8Ha-8Hc , in sulfuric acid.
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
The experim ental aN values for radical-dicatio ns 8Ha–8Hc and liter ature aNH values for
radical-cations 10a–10c corresponding to compounds 1a and 1c (by oxidation in acid
medium3,18,31-37 or in m olten salts32) are presented in Table 6 and its footnotes.

XH
NRa, X=S, R=H;
b, X=S, R=Cl;
c, X=O, R=H..+
10a-10c

We can ass ume that th e EPR spectra, λmax and color of the ne w radical-dications 8Ha-8Hc
should be comparable to t hose of the radical-cations 10a-10c3,18,31-37 (Table 6).

Table 6. EPR aN (or aNH) and g valu es, as well as electron ic ab sorption data for radical-dications
8Ha–8Hc (experim ental values ) and radical-cations 10a-10c (experim ental and/or literature data
values)
Radicals g aN (gauss) aNH (gauss) λmax(nm) Colorb
8Ha 2.0076 6.66 520bOrange-red
8Hb 2.0082 6.36 534bRed
8Hc 2.0057 8.90 540bRed-violet
10a 2.0050336.5233
6.4133
6.50337.07a
6.523,18,31
7.1032
7.532,33,36519b
51532,34 Orange-red
10b 7.10a529bRed
10c 2.004933 7.9033
7.83339.23a
9.8333
9.0232,37530b
52932,35 Red-violet
a our experim ental values in concentrated sulfuric acid.
b the colo r in a m ixture of benzene-acetone (1:1 v/ v) with five drops of concentrated H 2SO 4.

The red solutions of 4a–4c in concen trated sulfuric acid presenting the EP R spectra sh own i n
Figure 4 ref orm these com pounds on diluting with a 20-tim es larger am ount of water. The work-
up was extr action with dichlo romethane, dry ing of the colo rless organ ic layer, and evaporating
the solvent in vacuum . The pink-colored aqueous phase was neut ralized with NaHCO 3, and then
the sam e procedure was followed. Analysis of bot h residues by TLC revealed only the presence
of com pounds 4a-4c , proving that no degradation takes place in H 2SO 4 and that rad icals 8Ha-
8Hc have no structur al modifications.

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Hydrophobicity/hydro philic ity balance of the new Wurster az a-crown-ethers 4a –4c
The hydrophobicity/hydrophilici ty property of com pounds 4 is im portan t for their possib le
chem ical and biom edical app lications. Th e octanol-water partition coefficient ( P) and its
logar ithm (logP ) are th e usual param eters38 for estim ating quantitativel y these ch aracteris tics,
and they can be m easured or computed. In our case, this property for com pounds 4a–4c was
studied experim entally by reversed phase TLC39-43 (RP-TLC) and compared with this property
for the starting com pounds 1a–1c, 3, and the side-reaction com pound 7. Thus, Rf values were
measured using precoated C 18-chain layers ( RP-18F 254S, Merck ), as stationary phases and different
aceton itrile-water m ixtures as m obile pha ses (Table 7). The m olecular hydrophobicity, RM0,
appreciated as a resu lt of experim ental data depending on RM0 valu es and calcu lated39-43 with eqs.
1 and 2, is the RM value extrapolated to zero concentrat ion of the organic com ponent in the
aceton itrile –water m ixture; b is the change in the RM value caused by increas ing th e
concentratio n (K) of the organic com ponent in the m obile phase. Statistical analysis involved the
correlation coefficient ( R), the Fish er param eter (F), and the standard deviation ( SD) (Table 7).

RM = log(1/ Rf -1) eq. 1
RM = RM0 + bK e q. 2

Table 7. Rf values, hydrophobic characteristics ( RM0 and b) and calculated logP of the ne w
compounds 4, of the starting com pounds 1, 3 and of the secondary reaction product 7. RP-TLC
resultsa,b for aceton itrile-water m ixtures (A–E)
RfHydrophobici ty
characte ristics Statistical param eters
No.
A B C D E RM0 b R F SD logP
calc.
1a 0.789 0.717 0.650 0.584 0.487 2.190 –0.029 –0.998 902.1 0.015 4.150
1b 0.679 0.615 0.513 0.410 0.346 2.639 –0.031 –0.997 505.8 0.022 5.180
1c 0.831 0.769 0.669 0.641 0.512 2.379 –0.032 –0.988 129.1 0.044 3.840
3 0.743 0.692 0.675 0.623 0.602 0.879 –0.013 –0.984 95.8 0.022 0.950
4a 0.428 0.333 0.289 0.205 0.161 2.925 –0.029 –0.995 323.1 0.025 4.830
4b 0.342 0.220 0.189 0.129 0.103 3.336 –0.031 –0.986 106.7 0.048 5.420
4c 0.460 0.350 0.297 0.246 0.168 2.866 –0.029 –0.991 177.5 0.034 4.430
7 0.717 0.679 0.644 0.615 0.597 0.731 –0.011 –0.988 127.0 0.016 2.350
aFive determinations on silica gel RP-18F 254S (Merck), with p ercent of acetonitr ile in mixtur e
aceton itrile-water: A = 9 5%, B = 90%, C = 85%, D = 80% and E = 75%; bRM0, b, R, F, and SD
are defined by the preceding text and by eqs. 1 and 2.

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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
On attem pting to calc ulate log P values using fragm ental constants,44 a satisfactory
correlation with experim ental data for RM0 was obtained (Figure 5).

1 2345 60.51.01.52.02.53.03.5
4a4c
1c
1a1b4b
3
7Y=0.582X – 0.025
N = 8; R2 =0.867; SD =0.612 ; F =39.04; R2(CV) =0.844 RM0
logPcalcd.
Figure 5. RM0 vs logP calcd for com pounds 1a-1c , 3, 4a-4c and 7.

The experim ental results concerni ng the hydrophobic/hydrophilic character ( RM0 values,
Table 7 ) indicate th at the starting hetero cycles 1a–1c have a higher hydrophobicity than the
compounds 3 and 7 containing the N-phenylaza-15 crown-5, and that the new W urster aza-
crown-ethers 4a–4c are the m ost hydrophobic of all.

Conclusions

In a one-step synthesis, the free radicals 2a–2c obtained by oxidizing (with I 2, Fe3+ or Cu2+)
phenothiazine 1a, 2-chlorophenothiazine 1b, or phenoxazine 1c afford by homolytic aromatic
substitution of N-phenylaza-15-crown-5 3 new “W urster’s aza -crow n-ethe rs” 4a–4c. The
structures were confir med by m ass spectrometry, 1H-NMR and 13C-NMR spectra. Redox
reactions yielding the Wu rster radical-cations 8a–8c and the corres ponding dications 9a–9c were
explored by cyclic voltammetry. I n the pr esence of lithium and sodium cations, oxidation
potentials of 4a decrease, proving the ionophoric characte r of this new “Wurster’s aza-crown-
ether”. In concentrated s ulfuric acid stable radical-dications 8Ha–8Hc are for med, as proved by
EPR spectra. The hydrophobicity of the new “ Wurster’s aza-crown-ethers” 4a–4c was
determ ined experim entally by R P-TLC. Compounds 4a–4c may lead to an alytical and
bioanalytical applications.

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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
Experim ental Section

General. Phenothiazine 1a, 2-chlorophenothiazine 1b, phenoxazine 1c, N-methylphenothiazine,
iodine, ascorbic acid, CuCl 2.2H 2O, anhydrous sodium acetate, sodium thiosulfate, anhydrous
sodium sulfate, and lead dioxide were from Aldrich; N- phenylaza-15-crown-5 3, anhydrous
FeCl 3, NaClO 4.H2O, PLC plates S ilica Gel 60 F 254 (for Prepa rative TLC), TLC plates Silic a Gel
60 F 254 (for analytical TLC), and silica gel RP-18 F 254S (for RP-TLC), were from Merck;
FeCl 3.6H 2O, tetra-n-butylamm onium pe rchlo rate (TBAP) and tetram ethylammonium perchlorate
(TMAP) were from Fluka.

Instrumentation . 1H-NMR (300 MHz) and 13C-NMR spectra (100 MHz) were recorded with a
Varian Inova 400 with an ASW -SW headprobe at 30 șC. using uni dimensional techniques (Dept,
Apt) and bidim ensional sequences (G cosy, Ghm qc, Ghm bc, Ghsqc, where G m eans gradien t). IR
spectra were record ed with an FT-IR Bruker Vertex 70 equi pped with ATR diamond cell. ESI-
MS spectra were recorded with a QMD 1000 Carlo Erba instrum ent. Cyclic v oltammetric
measure ments were perfor med with a conventi onal three-electrode gl ass cell by m eans of a
PAR-273-A potentiostat, and all solutions were prepared by using acet onitrile. As reference
electrode, a silver wire immersed in a 0.1M AgNO 3 solution was u sed, linked to the m ain
compartment of the cell by m eans of a Vycor plug. A platinum disk (surface area, 0.0 7 cm2) and
a platinum wire were used as the work ing and counter electrode, respectively. The
voltamm ograms were recorded at a concentr ation of the investig ated com pounds of 10-3 M,
within the potential range –0.5 to 1.0 V. As supporting electrolyte, tetra-n-butylamm onium
perchlorate (TBAP), tetram ethyla mmonium perchlorate (T MAP), NaClO 4 or LiClO 4, were used,
at a concentration of 0.1M. EPR spectra were recorded at room temperature on a JE OL FA 100
spectrom eter with 100 kHz m odula tion freque ncy, 0.998 mW microwave power, 480 s sweep
time, 0.2 G m odulation amplitude, time constant 0.3 s. Com pounds 1a-1c and 4a–4c were
oxidized in H 2SO 4 to give the corres ponding radical-dications 8Ha –8Hc and radical-ca tions
10a–10c, respectively.

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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
Synthesis of compounds 4a–4c w ith various oxidiz ing age nts.

XNO O
O
NO
56781
2
3
49
1011121314
15
1617
1819202122 23
24
25
26
27
R
4a-4ca, R=H, X=S; b, R=Cl , X=S; c, R=H, X=O

A. Oxidation w ith iodine . Equimolar am ounts of arom atic heterocyc1es 1a–1c and N-
phenylaza-15-crown-5 3 were dissolved in methanol (30 mL for one gram of m ixture) at room
temperature. The pale y ellow so lution was treated with a so lution of iodine in methanol (m olar
ratio 1:1.5 f or 1:I2, i. e. 40 mL m ethanol for one gram of iodine) and left for 24 hrs with stirring
at room temperature. Then di stilled water (about ten tim es la rger volum e) wa s added to the
green-brown solution, when a fine brown preci pitate w as form ed. A solution of sodium
thiosulfate was added for com pletely rem oving i odine, followed by adding ascorbic acid till the
pH was 3.5. Solid sodium chloride was added to the grey suspension for obtaining an alm ost
saturated solution in order to f acilitate the precipitation. After keeping overnight at 5°C, the
precip itate was f iltered off with suction on a G3 glass f ilter and was hed with distilled water
(from the filtrate one m ay isolat e unreacted N-phenylaza -15-crown-5 3 with 20% yield, by
extra ction with m ethyle ne chlo ride, evapora tion of the solvent, and pu rification by TLC). The
precip itate was dissolv ed in m ethylene chlo ride and the extrac t was washed with 2% aqueous
thiosulfate, and then with 2% aqueo us ascorb ic acid. The yellow-green organic phase was dried
over sodium sulfate and then the solvent wa s rem oved under reduced pressure. The crude
compounds 4a–4c were purif ied by preparative TLC (PLC plates Silic a Gel 60 F 254,
dichlorom ethane: toluene: m ethanol, 5:5:0.2 v/v, four tim es). The extraction from silica gel was
perform ed in a Soxhlet with dichlorom ethane: methanol (9:1 v/v). Yields: 52% for 4a, 53% for
4b and 51% for 4c.
B. Oxidatio n with anhydrous iron(III) chlorid e. With the sam e molar ratios a s in the prev ious
procedure, the m ethanol solution was kept for 24 hrs at room te mperature under stirring. Then
distilled water (a 10-tim es larger volum e) was added, followed by ascorbic acid to pH = 3.5 and
by solid sodium chloride to reach an alm ost saturated solution. After keeping at 5°C overnight,
the solu tion was extrac ted with m ethylene chlo ride, the o rganic phase was dried o ver Na 2SO 4,
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
the solvent was rem oved and the products were isolated as indicated above. Yields: 31% for 4a
and 30% for 4c.
C. Oxidatio n with CuCl 2.2H 2O. The proced ure was similar to that outlin ed ab ove under B.
Yield: 50% for 4a.
10-(N,N' -4-Phenylene-a za-15-crown-5)-phenothiaz ine, 4a. Off-white crystals, m .p. 162-
164°C; ESI-MS, 492, calculated for C 28H32N2O4S, 492; Anal.: Calcd.% : C, 68.26; H, 6.54; N,
5.68; found% C, 68.21; H, 6.50; N, 5.61.1H-NMR (CDCl 3, δ ppm , J Hz): 7.16(d, 2H, H-12, H-
16, 9.0); 6.80(d, 2H, H- 13, H-15, 9.0); 6.95(dd, 2H, H- 4, H- 6, 1.6, 7.4); 6.84(td, 2H, H-2, H-8,
7.3, 1.6); 6.75(td, 2H, H-3, H-7, 7.4, 1.2); 6.26(dd, 2H , H-1, H-9, 1.2, 8.2); 3.82(t, 4H, H-22, H-
23, 6.1); 3.72÷3.64(m , 12H, H-19, H-20, H-21, H-24, H-25, H-26); 3.64(t, 4H, H- 18, H-27,
5.9).13C-NMR (CDCl 3, δ ppm ): 147.21(C-14); 145.04(C-1a, C-9a); 128.49(C-11); 119.38(C-C-
4a, C-6a); 131.74(C-12, C-16); 112.76(C-13, C-15); 126.78(C-2, C-8); 126.44(C-4, C-6);
121.94(C-3, C-7); 115.73(C-1, C-9); 71.32(C-22, C-23); 70.26(C-21, C-24); 69.95(C-20, C-25);
68.47(C-19, C-26); 52.83(C-18, C-27). FT-IR (ATR in solid, ν cm-1): 3055w; 2891s; 2868s;
1605m ; 1571w; 1514vs; 1458vs; 1439s; 1384m ; 1348m ; 1299s; 1231s; 1204w; 1189w; 1127vs;
1109s; 1087m ; 1062m ; 1044m ; 1007w; 977 m; 944m ; 755m ; 739s; 618w; 549w;
10-(N,N' -4-Phenylene-a za-15-crown-5)-2-chloro-phenothia zine, 4b. White-yellow crysta ls,
m.p. 171-172°C; ESI-MS, 527, calculated for C 28H31O4N2SCl: 527; Anal.: Calcd.%: C, 63.80; H,
5.92; N, 5.31; found% C, 63.78; H, 5.89; N, 5.28; 1H-NMR (CDCl 3, δ ppm , J Hz): 7.14(d, 2H,
H-12, H-16, 3J(H12(16)-H13(15))=9.0); 6.81(d, 2H, H-13, H-15, 3J(H13(15)-H12(16))=9.0); 6.94(dd, 1H,
H-6, 4J(H6-H8)=1.8, 3J(H6-H7)=7.4); 6.78(td, 1H, H-7, 3J(H7-H6, H7-H8)=7.4, 4J(H7-H9)=1.4);
6.82(m , 1H, H-8); 6.24(dd, 1H, H-9, 4J(H9-H7)=1.4, 3J(H9-H8)=8.2);;6.85(d, 1H, H-4, 3J(H4-
H3)=8.2); 6.73(dd, 1H, H-3, 4J(H3-H1)=2.1, 3J(H3-H4)=8.2); 6.26(d, 1H, H-1, 4J(H1-H3)=2.1);
3.83(t, 4H, H-22, H-23, 6.2) 3.72÷3.64( m, 16H, H-18÷H-21, H-24÷H-27).13C-NMR (CDCl 3, δ
ppm): 147.58(C-14); 146.22(C-1a); 144.47(C-9a); 132.65(C-11); 127.90(C-2); 119.19(C-6a) ;
117.98(C-4a); 131.46(C-12, C-16); 1 13.01(C-13, C-15);116.12(C-9); 115.70(C-1); 121.72(C-3);
122.46(C-7); 126.98(C-6); 127.04(C-8 or C-4); 126.47(C-4 or C-8); 71.36(C-22, C-23); 70.31(C-
21, C-24); 70.07(C-20, C-25); 68.5 5(C-19, C26); 52.82(C-18, C-27).FT-IR(ATR in solid, ν cm-
1): 3069w; 2970m ; 2846w; 1603m ; 1566m ; 1513s; 1483w; 1458vs; 1441m ; 1389s; 1361m ;
1349m ; 1291s; 1251m ; 1138s; 1109vs; 1043m ; 992m ; 956m; 927m ; 823m ; 743s; 561w.
10-(N,N' -4-Phenylene-15-crow n-5)-phenoxaz ine, 4c. Yellow crystals, m .p. 125-126°C; ESI-
MS, 476, calculated for C 28H32O5N2: 476; Anal.: Calcd.% C, 70.56; H, 6.76; N, 5. 87; found%
C, 70.52; H, 6.74; N, 5.80; 1H-NMR (CDCl 3, δ ppm, J Hz): 7.10(d, H-12, H-16, 8.6); 6.78(d, H-
13, H-15, 8.6); 6.65÷6.55(m , 6H, H-1, H-2, H-3, H-7, H-8, H-9); 5.99(m, 2H, H-4, H-6); 3.81(t,
4H, H-22, H-23, 6.0); 3.78÷3.65(m, 12H, H-19, H- 20, H-21, H-24, H-25, H-26); 3.64(t, 4H, H-
18, H-27, 5.9). 13C-NMR (CDCl 3, δ ppm ): 147.35(C-14); 144.02(C-4a , C-6a); 135.18(C-1a, C-
9a); 126.48(C-11);131.22(C-12, C-16); 123.18(C- 3, C-7); 120.74(C-2, C-8); 115.10(C-1, C-9);
113.32(C-4, C-6); 113.15(C-13, C-15);71.31(C -22, C-23); 70.26(C-21, C- 24); 69.97(C-20, C-
25); 68.48(C-19, C-26); 52.82(C-18, C-27). FT-IR (ATR in solid, ν cm-1): 3057w; 2935w;
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
2891m ; 2871m ; 1624w; 1604w; 1590w; 1516s; 1479vs; 1387w; 1350m; 1323s; 1289m ; 1265s;
1207w; 1129m ; 1111s; 1091m ; 1065w; 980w; 945w; 861w; 754m ; 740m; 584w;

Synthesis of compound 7

75 678
13
491011
12
13
14
1516172
IO
O
ONO

A 10% w/w solution of N-phenylaza-15-crown-5 3 in m ethanol was tre ated with a solution of
iodine in m ethanol (40 mL for one gram of I 2, molar ratio 1:1.5 for 3:I2). The brow n solution w as
stirred a t room tem perature f or 24 hrs. A tenf old la rger vo lume of distilled water was added,
when a fine brown precipitate separated. Then so lid sod ium thiosulf ate w as added under stirring
till the solution becam e colorless. After br inging the pH to 3.5 with solid ascorbic acid, the
suspension was kept overnight at 5°C. Solid s odium chloride was added to saturation, and the
solution was extracted with m ethylene chlo ride. After dry ing over Na 2SO 4, the solvent was
removed under reduced pressure. Purification was carried out by preparative TLC as outlined
above. Yield 74%.
N-(4-Iodop henyl)-az a-15-crow n-5, 7. Waxy pr oduct. ESI-MS, 421, calculated for C 16H24O4NI:
421; Anal.: Calcd.% C, 45.61; H, 5.74; N, 3.32; found% C, 45.59; H, 5.71; N, 3.30; 1H-NM R
(CDCl 3, δ ppm , J Hz): 7.43(d, 2H, H-3, H-5, 9.1); 6.44(d, 2H, H-2, H-6, 9.1); 3.72(t, 4H, H-12,
H-13, 6.2); 3.68÷3.63(m, 12H, H-9÷H-11, H-14÷ H-16); 3.55(t, 4H, H -8, H-17, 6.2); 13C-NM R
(CDCl 3, δ ppm ): 147.09(C-1); 137.71(C-3, C-7); 113.81( C-2, C-6); 76.30(C-4); 71.31(C-12, C-
13); 70.18(C -11, C-14); 70.09(C-10, C-15); 68.23(C-9, C-16); 52.50(C-8, C-9).

Monitoring the reactio n betw een 1a and 3 b y cyclic voltammetry. An equim olar m ixture of
compounds 1a and 3 in aceton itrile in the pres ence of TBAP was monitor ed analytica lly by
cyclic voltammetry following the redox processes (Figure 1). Then, on a dding a tenfold volum e
of distilled water to the solution, the m ilky li quid phase was extracted L/L with m ethylene
chloride. The lower phase wa s separated, dried over Na 2SO 4, and concentrated under reduced
pressure to about 0.1 m L. The TLC analysis co nfirm ed the m echanis m described by Schem e 2
by identifying the starting m aterials 1a, 3, of the reaction p roduct 4a (traces ), and of traces of
dimers 5a, 6a resulting f rom the free radical 2a.

TLC behav ior. TLC analyses (Table 8) were em ploye d for identification, purification, and
purity determ ination. For the dim ers 5a–5c and 6a–6c22,28 the ” fingerprint” test had used as
standard the solution obta ined by treating compounds 1a–1c with solid PbO 2 in m ethylene
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Genera l Papers ARKIVOC 200 9 (xiii) 342 -362
chloride; this solution contained unreacted com pounds 1a–1c and the dim ers (5a–5c + 6a–6c ).
On analytical silica gel 60 F 254 (Merck) p lates the three m obile ph ases (A –C) allowed th e
identificatio n of unreacted starting materials ( 1a–1c ), reaction products 4a–4c , dim eric side-
products 5a–5c , 6a–6c , and com pound 7. Detection of spots em ployed UV light (254 nm for
non-fluorescent background, or 366 nm for fluore scent background) as we ll as iodine vapor
yielding various colors indicated in T able 8.

Table 8. TLC data of compounds 1, 3-7 on silica gel analytical plates
Rf Detection
Com p. A B C UV
254 nm UV
366 nm Iodine vapor
1a 0.625 0.964 Grey Fl bGreen
1b 0.750 0.964 Grey Fl bGreen
1c 0.650 0.964 Grey Fl bBlue
3 0 0.317 0.285 Grey Yellow
4a 0 0.329 Grey Fl bPurple-g reen
4b 0 0.353 Grey Fl bGreen
4c 0 0.341 Grey Fl bOrange
5aa0.525 0.964 Grey Fl bGreen
6aa0.337 0.964 Grey Fl bGreen
5ba0.675 0.964 Grey Fl bGreen
6ba0.587 0.964 Grey Fl bGreen
5ca0.550 0.964 Grey Fl bGreen-blue
6ca0.475 0.964 Grey Fl bGreen-blue
7 0 0.470 0.380 Grey Yellow-brown
(A) toluen e: n-hexane=6 :4 (v/v ) twic e; (B) CH 2H2:toluene:MeOH=5:5:0.2 (v/v) four tim es; (C)
CHCl 3:MeOH=10:0.2 (v/v); aorder of migration ( Rf) by analogy with literature data;22,27 b Fl =
weakly fluorescent.

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