Surfactant effects on the reaction of 2-(4-cyano-phenoxy)-quinoxaline with hydroxide ion

Article abstract of DOI:10.1002/kin.20163

A reaction of 2-(4-cyanophenoxy)quinoxaline 1 with hydroxide ion is accelerated by supramolecular aggregates of cetyltrialkylammonium chlorides (alkyl = Me. n-Pr. and n-Bu). In diluted surfactant solutions, with relatively high substrate concentration (7.0 × 10^-5 M). rate constants go through double rate maxima with increase in the surfactant concentration. The first rate maximum is ascribed to a reaction occurring in premicellar aggregates and the second to reaction in micelles. At low substrate concentration (7×10^-6 M), second-order rate constants in the micellar pseudophase are dependent on the surfactant head-group size, which is related to charge dispersion in the transition state. Nonmicellizing tri-n- octylmethylammonium ions (TOAMs) increase the reaction of 1 with hydroxide ion. The observed rate enhancements may be due to the formation of small. Hydrophobic aggregates which bind the substrate and promote the nucleophilic substitution reaction.

Full text of DOI:10.1002/kin.20163

Surfactant Effects on the
Reaction of 2-(4-Cyano-
phenoxy)-Quinoxaline
with Hydroxide Ion
ANGELA CUENCA
Departamento de Qu ı´ mica, Universidad Sim o´ n Bol ı´ var, Apartado 89000, Caracas 1050, Venezuela
Received 19 October 2004; revised 23 May 2005; accepted 14 November 2005
DOI 10.1002/kin.20163
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: A reaction of 2-(4-cyanophenoxy)quinoxaline 1 with hydroxide ion is accelerated
by supramolecular aggregates of cetyltrialkylammonium chlorides (alkyl = Me, n-Pr, and n-Bu).
−
5
In diluted surfactant solutions, with relatively high substrate concentration (7.0 × 10 M),
rate constants go through double rate maxima with increase in the surfactant concentration.
The first rate maximum is ascribed to a reaction occurring in premicellar aggregates and the
−
6
second to reaction in micelles. At low substrate concentration (7 × 10
M), second-
order rate constants in the micellar pseudophase are dependent on the surfactant head-
group size, which is related to charge dispersion in the transition state. Nonmicellizing
tri-n-octylmethylammonium ions (TOAMs) increase the reaction of 1 with hydroxide ion. The
observed rate enhancements may be due to the formation of small, hydrophobic aggregates
which bind the substrate and promote the nucleophilic substitution reaction. ꢀC 2006 Wiley
Periodicals, Inc. Int J Chem Kinet 38: 510–515, 2006
INTRODUCTION
micelles as distinct reaction media [3–5]. The pseu-
dophase model considers reaction either in water or in
micelles, and predicts for bimolecular reactions single
rate maxima in the rate versus surfactant profiles. The
model is known to fail near the critical micelle concen-
tration (cmc) due to the pseudophase assumption [3].
One of the premises of the model is that there should be
no interactions between the monomeric surfactant and
the substrate, although there are evidences that they in-
teract at surfactant concentrations below the surfactant
cmc [1,2,7–9].
Previous studies [1,2] of nucleophilic heteroaromatic
substitution of quinoxaline derivatives in the presence
of cationic surfactants have provided evidence for the
existence of submicellar aggregates that are able to af-
fect reaction rates. In aqueous media, ionic surfactants
self-aggregate to form supramolecular structures that
bind reactants and alter reactivity [1–6]. Micellar ef-
fects on reaction rates and equilibria are generally de-
scribed by a pseudophase model which treats water and
In this study, we address the question of what
factors allow surfactant self-assemblies to alter re-
action rates. Nucleophilic heteroaromatic substitution
of 2-(4-cyanophenoxy)quinoxaline 1 (Scheme 1) with
OH was examined over a wide range of surfac-
tant concentrations, above and below the surfactant
Correspondence to: Angela Cuenca; e-mail: ancuenca@usb.ve.
Contract grant sponsor: Decanato de Investigaciones Cient ´ı ficas,
Universidad Sim o´ n Bol ´ı var, Caracas, Venezuela.
−
Contract grant number: DI-CB-S100117.
ꢀ
c 2006 Wiley Periodicals, Inc.

SURFACTANT EFFECTS ON THE REACTION OF 2-(4-CYANOPHENOXY)-QUINOXALINE
511
Scheme 1
−
5
Figure 1 Reaction of compound 1 (7.0 × 10 M) with
hydroxideioninthepresenceofCTACl. •[NaOH] = 0.03M;
cmc. Surfactants were hexadecyltrialkylammonium
chlorides, C16H33NR3Cl, R = Me (CTACl), R = n-Pr
ꢀ
[NaOH] = 0.003 M; ꢀ [NACl] = 0.025 M.
(CTPACl), and R = n-Bu (CTBACl).
Rate-Surfactant Profiles
Reaction at High Substrate Concentration. Figures 1
EXPERIMENTAL
Materials
−
5
−
and 2 show reaction of 1 (7.0 × 10 M) with OH
(0.003 and 0.03 M) in the presence of CTACl and
CTBACl, respectively. At this relatively high substrate
Compound 1 was synthesized in previous studies [10].
Preparation of TOAMs has been described in [11]. Sur-
factants were synthesized in the earlier work [12]. cmc
values were determined by variations in surface ten-
sion. In water, cmc values for CTACl and CTBACl are
concentration, first-order rate constants, k , for the
reaction of 1 with hydroxide ion go through double
rate maxima as surfactant concentration increases. Rate
effects occur at surfactant concentration below sur-
factant’s cmc in water. Reactions in the presence of
CTPAClshowthesamegeneraltendencies. Doublerate
maxima are suppressed on addition of NaCl.
ψ
1
.3 and 0.52 mM, respectively.
Hydrophobic organic substrates such as 1 lower the
surfactant cmc by inducing micellization, but this be-
havior does not explain the observed double rate max-
ima. A possible interpretation for the observed result
is that, in diluted surfactant solutions, the surfactant
aggregation induces the formation of premicelles that
interact with hydrophobic compound 1 and promotes
its nucleophilic substitution.
Surfactant self-association increases rates of bi-
molecular reactions in different ways [3,8]. Ionic
micelles speed bimolecular reactions by bringing reac-
tant together at the micellar surface. Premicelles may
activate compound 1 toward hydroxide ion through
the formation of transient substrate–ammonium ion
complexes. This behavior seems to be associated with
Kinetics
◦
Kinetic measurements were performed at 25.0 C in
a thermostatically controlled cell compartment of a
Perkin Elmer, lambda II spectrophotometer. Substrate
was added in MeCN so that the final solution contained
0.2 vol% organic solvent. Reactions were followed in
redistilled carbon dioxide free water. First-order rate
constants, kψ, are in reciprocal seconds. The reaction
was followed to infinity (10 half-lives) with correlation
coefficients ≥ 0.999. Rate constants are mean of three
measurements and agreed within 4%.
RESULTS AND DISCUSSION
Reaction in Water
−
In water, compound 1 reacts with OH to produce
2
-quinoxalone 2 (Scheme 1). The reaction of 1 with
hydroxide ion was followed at 362 nm by monitoring
◦
of 2-quinoxalone 2 at 362 nm. At 25.0 C, the second-
order rate constant value for the reaction of compound
−
3
−1 −1
1
with hydroxide ion is 2.17 × 10
M s . In some
cases, reactions were also followed by monitoring the
appearance of 4-cyanophenoxide ion at 276 nm. Ki-
netic rate constants obtained by monitoring λmax were
in agreement within 3% error.
−5
Figure 2 Reaction of compound 1 (7.0 × 10 M) with hy-
droxide ion in the presence of CTBACl. [NaOH] = 0.03 M;
•
ꢀ [NaOH] = 0.003 M; ꢀ [NACl] = 0.025 M.

512
CUENCA
sparingly water-soluble, hydrophobic substrates whose
association with amphiphilic ions decreases hydrocar-
bon water contact and provides ion–dipole interactions.
Substratehydrophobicityseemstobenecessary, butnot
a sufficient condition for the observation of double rate
maxima. Asingleratemaximaisgenerallyobservedfor
most micellar-assisted reactions. A specific interaction
between cationic headgroups and solute might explain
the double rate maxima if this interaction leads to the
formation of premicelles. It is known that quaternary
ammonium headgroups interact favorably with arenes
micelles. One remarkable difference between catalysis
by micelles and premicelles is that at a given concen-
tration, micelles are relatively uniform in size and their
structures are not very sensitive to reactants, provided
that the surfactant concentration is in large excess over
reactants. In diluted surfactant solution and at relatively
highsubstrateconcentration, thesurfactantaggregation
may be assisted by a cooperative interaction with so-
lute, whereas micellization does not require such an
interaction.
Values of the first rate maxima are higher than those
of the second maxima (Figs. 1 and 2). In Table I a com-
parison is been made between rates in micelles, kmic,
and in premicelles, kpre. kpre was estimated in very di-
luted surfactant solutions by equalizing its value to the
highest value of kψ (first maximum). Measurements of
kmic were made at surfactant concentrations well above
the cmc, where compound 1 was fully micellar bound.
Results show that reactions in premicelles are faster
than in micelles. This result is consistent with a very
strong interaction between substrate and surfactant in
premicelles, and a relatively loose organization of sub-
strate in the water-rich interfacial region of a cationic
micelle.
[7,13]. Submicellaraggregatesareinvolvedinsomenu-
cleophilic aromatic [8] and heteroaromatic [1,2] substi-
−
tution reactions, and in the attack of OH on thiophos-
phinates [14] where double rate maxima are observed
in rate versus surfactant profiles.
The dependence of the first-order apparent rate con-
stant with solute concentration suggests that small
aggregates of reactants and surfactant are present in so-
lution, rather than 1:1 adducts, and it appears that there
is a cooperative interaction between catalyst and reac-
tants. Micelles have well-defined structures which are
not markedly perturbed by addition of substrate, but
structures of small submicellar aggregates are prob-
ably very sensitive to low concentration of solutes
which may bind to them. In diluted surfactant, kψ in-
creases with the substrate concentration, and therefore
the formation of catalytically active submicellar clus-
ters might be induced by the substrate. Compound 1
may interact with amphiphilic cations to form clus-
ters or premicelles that would attract more hydrophobic
solute. Both substrate binding and chemical reactivity
should increase with the increasing cluster size.
Rates in premicelles should be much faster than in
water if pairing between cationic headgroup and hy-
droxide ion partially excludes water from the latter.
Premicelles must have a significant rate effect, because
if these assemblies were kinetically less effective than
micelles, rates will increase monotonically to a sin-
gle rate maximum as premicelles are converted into
Figures 1 and 2 show the suppression of the double
rate maxima by addition of NaCl. Chloride ion inhibits
−
reaction by competing with OH and decreases the
cmc converting submicellar aggregates into micelles.
Hydroxide ion is a hydrophilic ion with high charge
density that is probably weakly bound to submicellar
aggregates as it has been found with cationic micelles
[15].
Figure 3 shows the first-order rate constants for
the reaction of compound 1 with hydroxide ion
in the presence of nonmicellizing mesylates. Tri-n-
octylmethylammonium ions (TOAMs) speed the reac-
tion of compound 1 with hydroxide ion, although these
ions do not form micelles. Observed rate enhancements
may be due to the formation of clusters of hydropho-
bic ammonium ions which associate with the substrate
Table I Reaction of Compound 1 with Hydroxide Ion in Micelles and Premicellesa
×
103kψ (s
−1
)
2
b
×
10 NaOH (M)
Surfactant
Micelles (kmic)
Premicelles (kpre)
0
3
0
3
0
3
.3
.0
.3
.0
.3
.0
CTAC
CTAC
CTPAC
CTPAC
CTBAC
CTBAC
2.1
2.9
3.2
4.1
5.3
4.4
2.5
5.1
4.2
4.8
6.6
5.5
a
b
◦
−5
At 25.0 C and with 7.0 × 10 M substrate.
Values are from maximum values of k in Figs. 1 and 2.
ψ

SURFACTANT EFFECTS ON THE REACTION OF 2-(4-CYANOPHENOXY)-QUINOXALINE
513
Scheme 2
these reaction conditions, nucleophilic heteroaromatic
−
substitution of compound 1 with OH occurs in mi-
celles. At low substrate concentration, rate-surfactants
profiles can be fitted quantitatively to equations which
describe reactant distributions in terms of Scheme 2,
where subscripts “w” and “M” denote the aqueous and
−
5
Figure 3 Reaction of compound 1 (7.0 × 10 M) with
hydroxide ion in the presence of TOAMs. [NaOH] = 0.03 M.
and activate it toward nucleophilic heteroaromatic sub-
stitution. Rate enhancements by these nonmicellizing
salts have been observed in other bimolecular reac-
tions [1,3,11] and decarboxylation [16]. Compound 1’s
solubility is largely increased on addition of very small
amounts of TOAMs suggesting an association between
the substrate and the hydrophobic cations.
−
micellar pseudophase, S is the substrate, OH is the
nucleophile, KS is the substrate–surfactant binding
constant, Dn is the micellized surfactant whose concen-
tration usually is taken as that of total less monomeric
ꢁ
ꢁ
surfactant. kW and k are, respectively, the first-order
M
rate constants in aqueous and micellar pseudophases.
The overall observed first-order rate constant, kψ, is
given by Eq. (1) [4]:
Reaction at Low Substrate Concentration. At rela-
ꢀ
ꢁ
−
6
ꢁ
−
tively low substrate concentration (7.0 × 10 M), rate
versus surfactant concentration profiles for the reaction
of compound 1 with hydroxide ion show a single rate
maximum (Figs. 4 and 5), a typical behavior for mi-
cellar assisted bimolecular reactions [3,5]. Reactions
in CTPACl show the same general tendencies. Under
k K OH
M
s
M
kꢁ =
(1)
1
+ KS([Dn] − cmc)
First-order rate constants can be written as second-
order rate constants, kW and kM, with the concentration
−
of OH in the micellar pseudophase written as a mole
fraction:
ꢀ
ꢁ
ꢁ
−
k
= kW OH
(2)
W
W
ꢀ
ꢁꢂ
ꢁ
OH
M
OH
M
k = kMm
= kM OH
([D] − cmc) (3)
M
−
[
OH w] is molarity in terms of total solution volume.
At low substrate concentration, rate data for reaction
−
of OH with compound 1 in solutions of cationic sur-
factants can be described using a pseudophase model
−
(
Eqs. (1)–(3)), in which the distribution of OH and
−6
Figure 4 Reaction of compound 1 (7.0 × 10 M) with
hydroxide ion the presence of CTACl. • [NaOH] = 0.03 M;
−
Cl between the aqueous and micellar pseudophases
is written in terms of the mass-action-like equations
ꢀ
[NaOH] = 0.003 M. Curves are calculated.
(4) and (5) [15]
ꢀ
ꢁꢂꢃꢄꢀ
ꢁꢄ
ꢀ
ꢁ
ꢀ
ꢁꢅꢆ
ꢁ
−
−
−
−
K
= OH
OH
[Dn] − OH − Cl
OH
M
W
M
M
(
4)
ꢀ
ꢁꢂꢃꢄꢀ
ꢁꢄ
ꢀ
ꢁ
ꢀ
ꢁꢅꢆ
ꢁ
−
ꢁ
ꢁ
ꢁ
K
= Cl
Cl
[Dn] − OH − Cl
Cl
M
W
M
M
(
5)
Table II gives values of the parameters that best fit
the experimental results for the reaction of compound
1 in cationic micelles. Solid lines in Figs. 4 and 5 repre-
sent values of kꢁ calculated using these parameters by
Eqs. (1), (4), and (5). At low substrate concentration,
−6
Figure 5 Reaction of compound 1 (7.0 × 10 M) with
hydroxide ion the presence of CTACl. • [NaOH] = 0.03 M;
ꢀ
[NaOH] = 0.003 M. Curves are calculated.

514
CUENCA
Table II Fitting Parameters for the Reaction of Substrate 1 with Hydroxide Ion in Micellized Surfactantsa
2
−
ꢁ
4
m
×
10 [OH ]
K
× 10 cmc
kM
−1
× 10k2
T
Cl
Surfactant
(M)
(M 1)
−
(M)
(s
)
(M
−1 −1
s
)
CTACl
CTACl
CTPACl
CTPACl
CTBACl
CTBACl
0.3
3.0
0.3
3.0
0.3
3.0
115
115
60
60
48
6
6
4
4
3
3
1.9
1.9
4.1
4.1
5.2
5.2
2.5
2.5
5.7
5.7
7.2
7.2
48
a
◦
= 9500 M−1, k
= 2.17 × 10−3
−1 −1
, K = 55, 25, and 12 M−1 for CTA , CTPA , and CTBA , respectively.
ꢁ
+
+
+
At 25.0 C and with K
s
W
M
s
OH
15
Substrate] = 7.0 × 10−6 M.
[
the model adequately describes rate data for reactions
of OH with compound 1, as shown in Figs. 4 and 5.
The Langmuir parameters, KOH, are from the litera-
sition state as in aromatic nucleophilic substitution and
E2 reactions [19]. The extent of the effect is increased
by increasing bulk of the surfactant headgroup. For
the nucleophilic heteroaromatic substitution of com-
−
ꢁ
+
+
ture [17] (K = 55 and 12 for CTA and CTBA , re-
OH
ꢁ
−
spectively). K , kM, and KS were treated as adjustable
pound 1 with OH , there should be extensive charge
Cl
−4
parameters. Kinetic cmc values are 7 × 10 M, 5 ×
dispersion in the transition state through the quinoxa-
line π system, consequently micellar assistance should
increase with the bulk of the headgroup.
−4
−4
1
0
M, and 4 × 10 M for CTACl, CTPACl, and
CTBACl, respectively, and with 0.03 M NaOH and
−
6
7
.0 × 10 M substrate concentration.
In conclusion, studies of surfactant effects upon re-
action rates should cover a wide range of surfactant
concentration below and above the surfactant cmc in
order to identify the nature and role of the supramolec-
ular structures affecting rates. In very diluted surfactant
solutions, quinoxaline derivative 1 forms associative
complexes with submicellar aggregates. These surfac-
tant clusters do not form a discrete reaction region but
promote reactivity by their association with the sub-
strate. An increase in the headgroup size favors nu-
cleophilic heteroaromatic substitution reactions where
charge is dispersed in the transition state.
Second-order rate constant, kM, for the reaction in
the micellar pseudophase has dimensions of reciprocal
time, and cannot be compared directly with second-
order rate constant in water, kW, the units of which are
−
1
−1
. Second-order rate constants in the
generally M
s
m
micellar pseudophase with the same dimensions, k ,
2
−
1
−1
s are given by Eq. (6):
M
m
k = kMVM
(6)
2
where VM is the molar volume of the reactive region
at the micellar surface, and the value VM = 0.14 L was
taken (estimates of VM range from 0.14 to 0.35 L) [5b].
The author thanks Lic. Gabriel Campos for the synthesis of
compound 1.
m
Values of k2 are based on constant VM. This value
may increase with increasing bulk of the alkyl group.
However, for reactions in hexadecyltributylammonium
bromide, Bacaloglu et al. [18] found NMR evidence
that indicates that VM does not change markedly with
alkyl group bulk because butyl groups do not extend
into the water but are “folded-back” toward the micellar
surface to reduce water-alkyl group contact.
Substrate orientation or location may also be influ-
enced by headgroup size. Increase in the bulk of the
surfactant headgroup should move the reaction center
more deeply into the interfacial region.
Rate enhancements for the alkaline hydrolysis
of compounds 1 follow the sequence: CTACl <
CTPACl < CTBACl (Table II). Several factors may al-
ter the rate of a reaction occurring in micelles with
bulky headgroups. There is evidence that headgroup ef-
fects on reactivities are larger for bimolecular reactions
which have extensive charge delocalization in the tran-
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