Dissociation of aryl sulfonyl phthalimide radical anions: Relevance to the biological activity of aryl sulfonyl amides

Article abstract of DOI:10.1039/c2cc36835h

The reduction of two aryl sulfonyl phthalimides leads to the corresponding radical anions. Surprisingly, that of the nitro-derivative decomposes faster than that of the methyl derivative. A theoretical investigation along with application of the dissociat

Full text of DOI:10.1039/c2cc36835h

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COMMUNICATION
Dissociation of aryl sulfonyl phthalimide radical anions: relevance to the
biological activity of aryl sulfonyl amidesw
Abdelaziz Houmam* and Emad M. Hamed
Received 16th July 2012, Accepted 4th October 2012
DOI: 10.1039/c2cc36835h
The reduction of two aryl sulfonyl phthalimides leads to the
corresponding radical anions. Surprisingly, that of the nitro-
derivative decomposes faster than that of the methyl derivative.
A theoretical investigation along with application of the disso-
ciative ET theory to the decomposition of radical anions allows
rationalization of this unexpected behavior.
radical anion which undergoes the bond dissociation. Considerable
attention has been given to the dissociation processes of radical
anions due to their importance in many chemical and biochemical
8
processes such as the formation of Grignard reagents,
9 10
RN1 reactions and DNA damage. Two main dissociation
S
mechanisms can take place: a homolytic cleavage where the extra
electron remains on the initial host moiety and a heterolytic
cleavage where the extra electron is transferred to a leaving group
The biological activity of sulfonamides, also known as ‘‘sulfa
´
across the cleaving bond. Saveant demonstrated that both these
2
drugs’’, and related compounds having an N–SO functional group,
dissociation pathways can be accounted for through the extension
6,7,11–13
of his dissociative ET theory.
is well-known. They are widely used in both veterinary and human
1
medicine. Sulfonamides were also heavily used in feed additives to
These dissociation models were
1
promote the growth rate and weight gain of food animals. As a
successfully applied for various organic compounds including
11,14
aromatic halides,
15
benzylthiocyanates, and sulfenyl chlorides.
16
consequence, they have been frequently detected, in recent years, in
2
both municipal wastewater and surface water bodies. Aryl sulfonyl
The electrochemical reduction of compounds 1 and 2 was
studied by cyclic voltammetry (CV) in acetonitrile, in the presence
piperazines have shown important antibacterial activity against
3
susceptible and resistant Gram-positive pathogenic bacteria. Aryl
4 6
of tetrabutylammonium hexafluorophosphate (Bu NPF 0.1 M)
4
sulfonyl indoles have also shown important anti-HIV1 activity. An
at a glassy carbon electrode. The peak characteristics (peak, E
0
and standard, E , potentials, peak width (E
p
,
ꢀ Ep/2), and deduced
interesting point in both these cases is that the activity is dependent
on the nature of the substituent on the aryl group. It has been
shown that the nitro-substituted compounds are more active than
other derivatives including the methyl-substituted ones.
p
transfer coefficient, a) are summarized in Table 1.
Fig. 1a shows the cyclic voltammogram corresponding to the
reduction of compound 1. The first peak is observed at a potential
Ep1 = ꢀ1.21 V/SCE, and its height, measured with reference to the
monoelectronic wave of ferrocene, corresponds to the consumption
of 1.1 electrons per molecule. The transfer coefficient value deter-
Here we report an investigation of the reduction of two aryl
sulfonyl amides. This investigation may help understand the
previously reported difference in the biological activity of aryl
sulfonyl amides. It will also allow determination of the reduction
mechanisms and products, which are important for addressing the
water contamination issue. The investigated compounds are the
1
7,18
mined from the first reduction peak width
pointing to the formation of a radical anion.
scan after the first reduction peak shows indeed a quasi-reversible
corresponds to 0.9,
6,7,13
Reversing the
ꢁ
ꢀ
wave and confirms the formation of the radical anion (1 ).
A second reduction peak is observed at a peak potential Ep2
4-methyl and the 4-nitrophenyl sulfonyl phthalimides (Chart 1).
=
ET induced bond dissociation reactions undergo one of the two
5–7
ꢀ1.90 V/SCE and corresponds to the reduction of this radical
main pathways. The bond dissociation can be simultaneous with
5–7
concerted ET) or subsequent to (stepwise ET) the initial ET.
ꢁ
ꢀ 2ꢀ
anion (1 ) to the corresponding dianion (1 ). The dianion is
mostly protonated while only a very small fraction decomposes, as
indicated by the very small third (Ep3 = ꢀ2.19 V/SCE) and forth
(
The latter mechanism involves the intermediate formation of a
(
Ep4 = ꢀ2.58 V/SCE) reduction peaks corresponding to the
reduction of the phthalimidyl anion, by comparison with an
ꢀ
1
authentic sample. Upon increasing the scan rate to 5 V s the
first reduction wave becomes totally reversible. With a further
ꢀ1
Chart 1 Phenyl sulfonyl phthalimides 1 and 2.
increase to 40 V s both the first and second reduction waves
become reversible and the third and fourth reduction peaks totally
disappear (Fig. 1). This is an indication that for 1 the product of the
first ET, the radical anion, and that of the second ET, the dianion,
are both stable within the CV time scale.
University of Guelph, Guelph, Ontario N1G 2W1, Canada.
E-mail: ahoumam@uoguelph.ca; Fax: +1 519 766 1499;
Tel: +1 519 824 4120
w Electronic supplementary information (ESI) available: Theoretical
data, thermodynamic and kinetic expressions, and experimental part.
See DOI: 10.1039/c2cc36835h
The 4-nitrophenyl sulfonyl phthalimide (2) shows a different
behaviour (Fig. 1c). A first irreversible reduction peak is
1
1328 Chem. Commun., 2012, 48, 11328–11330
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Table 1 Electrochemical characteristics of the 4-methylphenyl (1) and 4-nitrophenyl (2) sulfonyl phthalimides
a
p1 (V vs. SCE) n (e mol
ꢀ
ꢀ1
0
E (V/SCE)
a
/2 (mV)
b
a
a
a
a
ArSCl Substituent
E
)
E
p
ꢀ E
p
E
p2 (V/SCE)
E
p3 (V/SCE)
E
p4 (V/SCE)
1
2
Me
NO
ꢀ1.21
ꢀ0.78
1.1
2.02
ꢀ1.18
ꢀ0.83
ꢀ52
0.90 ꢀ1.90
0.87 ꢀ1.16
ꢀ2.19
ꢀ2.03
ꢀ2.58
ꢀ2.20
2
ꢀ54
a
ꢀ1
b
At v = 200 mV s
.
Deduced from the peak width value.
Fig. 2 LUMOs of compounds (a) 1 and (b) 2.
the dissociation mechanism for all these compounds does not
change upon changing the structure. We will show that this is
not the case for the presently investigated sulfonyl phthalimides.
To gain more insight into the nature of the initial ET and
understand the difference in stability of the radical anions, as a
function of the substituent on the aryl ring, a theoretical study at the
22
B3LYP level of compounds 1 and 2 was performed. The LUMOs
of the two compounds are shown in Fig. 2. A very important result
is that while the LUMO of the 4-methyl substituted compound (1)
is located on the phthalimidyl group, that of the 4-nitro substituted
one (2) is located on the nitrophenyl moiety. This difference has
important implications in the observed difference in behavior.
Another important parameter is the bond dissociation energy of
the N–S chemical bond which shows nearly no dependence on the
nature of the substituent. The calculated values are 58.73 and
Fig. 1 CV in CH
3 4 6
CN + NBu PF (0.1 M) on a glassy carbon
ꢀ1
electrode of compound 1 (1.68 mM), (a) scan rate v = 0.2 V s
ꢀ
1
ꢀ1
and (b) v = 40 V s and compound 2 (1.23 mM), (c) v = 0.2 V s
ꢀ
1
.
and (d) v = 80 V s
observed at ꢀ0.78 V/SCE, corresponding in this case to the
consumption of 2 electrons per molecule, measured with reference
to the monoelectronic wave of ferrocene. This is an indication of
the instability of the corresponding radical anion in this CV time
scale. This peak quickly becomes reversible when the scan rate is
ꢀ
1
59.28 kcal mol for compounds 1 and 2, respectively. This
indicates at least that the observed difference cannot be
rationalized simply in terms of the N–S bond strength. The
introduction of a nitro group into 2 totally shifts the location
of the LUMO to the aryl moiety, and once the radical anion
ꢀ
1
0
increased to 80 V s , with a standard reduction peak E = ꢀ0.83
V/SCE, less negative than that corresponding to compound 1, as
expected. A second reversible peak is observed at ꢀ1.16 V/SCE
and corresponds to the reduction of the 4-nitrophenyl sulfinate
anion, generated by dissociation of the N–S bond upon reduction
at the first peak. This is confirmed by the electrolysis of 2 at a
ꢁ
ꢀ
(2 ) is formed, the electron is transferred from the p* of the
nitrophenyl group to the s N–S bond.
potential E = ꢀ0.78 V vs. SCE, which shows the formation of
To understand the difference in behavior between 1 and 2, it is
important to determine the dissociation mechanism, otherwise
whether the cleavage is homolytic or heterolytic (Scheme 1). A
homolytic cleavage means that the injected electron would
remain on the same hosting group as a result of the dissociation.
The heterolytic cleavage means that the dissociation would be
accompanied by a transfer of the injected electron from the
initially hosting group to the opposite site of the structure. A
comparison of the oxidation potentials of the two potential
anions (phthalimidyl and aryl sulfinate) allows determination of
this dissociation mechanism. The oxidation potentials of the
p
the phthalimidyl anion and the 4-nitrophenyl sulfinate anion. A
second reduction peak of the 4-nitrophenyl sulfinate is observed at
ꢀ
2.03 V/SCE which overlaps with the reduction peak of the
phthalimidyl anion observed at ꢀ2.2 V/SCE.
The CV data clearly indicate that the radical anion of
the 4-methylphenyl sulfonyl chloride is more than 2 orders of
magnitude more stable than that corresponding to the 4-nitro
ꢁ
ꢀ
ꢁ
ꢀ
compound. The faster decomposition of 2 compared to 1 is
intriguing since it is generally expected that introduction of a NO
2
group would have the opposite effect. The presence of a nitro
group on the aryl ring of aromatic halides for example lowers the
sulfinate anions (E0
ꢁ
ꢀ
¼ 0:65 V=SCE and
O2NPhSO2 =O NPhSO2
11,14
decomposition rate of the corresponding radical anions.
2
For
23
0
E
ꢁ
ꢀ
¼ 0:45 V=SCE) were determined by CV.
CH3PhSO2 =CH PhSO2
3
benzyl halides, the presence of a nitro group on the aryl ring also
provides a more stable radical anion to a point that a transition
in the ET mechanism (from concerted, for electron donating
1
9
substituents, to stepwise, for the nitro group) is observed.
A
20
similar result was reported for aromatic thiocyanates and
2
1
sulfenyl chlorides. Correlations between the fragmentation
rate constants of the radical anions and the standard reduction
1
potential of a large series of aryl bromides and aryl chlorides
4
11
clearly show a faster cleavage for compounds presenting a more
negative standard reduction potential. It is worth noting that
ꢁ
ꢀ
ꢁ
ꢀ
Scheme 1 Potential dissociation mechanisms of 1 and 2 .
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11328–11330 11329

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The phthalimidyl anion showed no oxidation potential up to
V/SCE indicating an oxidation at least 1.35 V more difficult
than that of the sulfinate anions. This large difference indicates
investigation shows that changing the substituent from the
methyl to the nitro group does not only decrease the energy of
the LUMO but also completely changes its location from the
phthalimidyl group to the aromatic ring. Analysis of the
kinetics through application of the extension of the dissociative
ET theory to the case of the decomposition of radical anions
shows contribution of different parameters to the intrinsic
barrier of the decomposition of the two radical anions. Further
investigations of a larger series of compounds and of other
derivatives can provide more insight into the relationship
between the ET characteristics and the biological activity. From
a synthetic point of view, this can help in designing adequate
structures with optimum activity.
2
ꢁ
ꢀ
ꢁ
ꢀ
that the decomposition of both 1
phthalimidyl anion and a 4-substituted phenyl sulfonyl radical
pathway A in Scheme 1). Keeping in mind the difference in
the location of the injected electron in the two compounds, this
and 2
leads to a
(
ꢁ
ꢀ
indicates that while the dissociation of 1 is homolytic that of
ꢀ
ꢁ
2
is heterolytic. This difference in the mechanism can have
implications on the kinetics of the dissociation as has been
4
2
previously shown for other compounds.
ꢀ
ꢁ
ꢁ
ꢀ
Finally, the decomposition of 1 and 2 can be understood
by comparing their thermodynamics and their kinetics using the
6,7,11–13
extensions of the dissociative ET.
The driving force is only
slightly different for the two dissociation modes (see ESIw). The
ꢁ
ꢀ
is
Notes and references
intrinsic barrier for the homolytic decomposition of 1
described by eqn (1), which depends on the oxidation potential
ꢁꢀ, the standard reduction potential
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of the leaving group E0
X =ðX Þ
ꢁ
ꢁ
2
of 1, the bond dissociation energy of the N–SO bond at the
level of 1 (DRX), and the entropy variation. Here RX represents
the initial compound where X represents the phthalimidyl group.
ꢀ ꢀ
ꢁ ꢁ
(
X ) represents an excited state of the phthalimidyl anion (X )
that results from the injection of an electron into the low lying
phthalimidyl radical orbital.
4
L.-L. Fan, W.-Q. Liu, H. Xu, L.-M. Yang, M. Lv and
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1
4
l0
4
5 A. Houmam, Chem. Rev., 2008, 108, 2180.
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´
7 J.-M. Saveant, Elements of Molecular and Biomolecular Electro-
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8 H. Hazimeh, F. Kanoufi, C. Combellas, J.-M. Mattalia,
C. Marchi-Delapierre and M. Chanon, J. Phys. Chem. C, 2008,
DGa0
¼
ðDRX þ E
0
RX=RX
0
ꢁꢀ þ TDSÞ þ
ꢀ
ð1Þ
ꢁꢀ ꢀ E
ꢁ
ꢁ
;hom
X =ðX Þ
´
1
4
l0
4
DGa0
¼
ðDRX þ E
0
RX=RX
0
ꢁꢀ þ TDSÞ þ
ꢀ
ð2Þ
ꢁꢀ ꢀ E
ꢁ
ꢁ
;het
R =ðR Þ
ꢁ
ꢀ
The intrinsic barrier for the heterolytic decomposition of 2 is
also expressed in terms of the bond dissociation energy of 2,
which is comparable to that of 1 (eqn (2)). It also involves the
standard reduction potential of 2, similar to eqn (1), which is less
negative than that corresponding to 1 and hence slightly increases
the intrinsic barrier for the former compound. The main difference
however is the total independence of the intrinsic barrier in this case
1
12, 2545.
(a) P. Boy, C. Combellas, C. Suba and A. Thie
1994, 59, 4482; (b) C. Amatore, C. Combellas, N.-E. Lebbar,
A. Thiebault and J.-N. Verpeaux, J. Org. Chem., 1995, 60, 18.
9
´
bault, J. Org. Chem.,
´
1
0 (a) H. Abdoul-Carime, M. Huels, E. Illenberger and L. Sanche,
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on E0
ꢁꢀ. It involves rather the standard oxidation potential
ꢁ
ꢁ
X =ðX Þ
of the nitrophenyl sulfinate E
0
11 J.-M. Save
12 J.-M. Save
13 J.-M. Saveant, Dissociative Electron Transfer, in Advances in
´
´
´
ant, J. Phys. Chem., 1994, 98, 3716.
ant, Tetrahedron, 1994, 50, 10117, report no. 360.
ꢁ
ꢀ
¼ 0:65 V=SCE
O2NPhSO2 =O NPhSO2
2
which is a lot less positive than that corresponding to
the phthalimidyl anion (>2 V/SCE). This big difference
counteracts that of the standard reduction potentials of the
parent molecules and greatly lowers the intrinsic barrier of the
Electron Transfer Chemistry, ed. P. S. Mariano, JAI Press,
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´
4 C. Costentin, M. Robert and J.-M. Saveant, J. Am. Chem. Soc.,
1
2
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ꢁ
ꢀ
decomposition of 2 . The solvent reorganization energy is not
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very different for the two modes as the dissociation leads to
6,7,11–13
similar fragments.
1
Therefore the change in the LUMO
1
location, as a function of the substituent on the aryl ring, affects
the dissociation mechanism and more importantly the associated
intrinsic barrier causing this unexpected behaviour.
17 a = (RT/F)(1.85/E /2 ꢀ E ).
p
p
1
8 (a) J.-M. Save
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´
ant, J. Am. Chem. Soc., 1992, 114, 10595;
(
´
1
´
In summary, the reduction of the investigated compounds
leads to the formation of the corresponding radical anions.
With the methyl substituent the radical anion is stable enough
within the CV time scale that a second electron is added
producing the dianion. With the NO2 electron withdrawing
group, the radical anion surprisingly decomposes much faster
to the phthalimidyl anion and the sulfinate radical. This
behavior is in accordance with the higher biological activity
observed for the nitro substituted sulfonamides. The theoretical
2
2
2
2
2
2
1
4 P. Maslak, J. N. Narvaez and T. M. Vallombroso, Jr., J. Am.
Chem. Soc., 1995, 114, 12373.
1
1330 Chem. Commun., 2012, 48, 11328–11330
This journal is c The Royal Society of Chemistry 2012