Differences in the activity of neutral and ionized β-cyclodextrin on the nitrosation of amines by phenylpropyl nitrites

Article abstract of DOI:10.1039/b005647m

The influence of β-cyclodextrin (β-CD) on the base-catalyzed hydrolysis reaction of 1-phenyl-1-propyl, 2-phenyl-1propyl and 3-phenyl-1-propyl nitrites and on the nitrosation of pyrrolidine, piperidine and N-methylcyclohexylamine by the aforementioned alkyl nitrites (RONO) is studied in aqueous buffers of the amines and in an alkaline medium with [OH^-] = 0.20 M. The hydrolysis reaction is catalyzed by the presence of β-CD owing to the formation of reactive 1:1 inclusion complexes between the alkyl nitrite and the ionized β-CD; the addition of potential inhibitors, such as dodecyltrimethylammonium bromide monomers, accelerates the reaction even more. The effect is quite significant in the case of 1-phenyl-1-propyl nitrite and is viewed as a case of allostery. In the presence of neutral β-CD, the nitrosation by 1-phenyl-1-propyl nitrite, either of pyrrolidine or piperidine, is inhibited by β-CD addition; however, the nitrosation reaction of piperidine by 2-phenyl-1-propyl nitrite is catalyzed (passing through a maximum) by β-CD, whereas the nitrosation of pyrrolidine promoted by 3-phenyl-1-propyl nitrite exhibits practically no change upon β-CD addition. In alkaline media (containing ionized β-CD) the nitrosation of pyrrolidine by 1-phenyl-1-propyl nitrite is inhibited by the presence of β-CD; in contrast, the nitrosation of both piperidine and N-methylcyclohexylamine is catalyzed in all cases, but the degree of catalysis depends not only on the alkyl nitrite structure, but also on the type and concentration of the amine. Kinetic results are quantitatively interpreted on the basis of the proposed reaction mechanism in each case, and the kinetic rate constants of the different steps are determined. Comparison of the results obtained in aqueous alkaline media and in aqueous buffers of the amines themselves allows us to establish important characteristics of the transition state of the reaction.

Full text of DOI:10.1039/b005647m

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Di†erences in the activity of neutral and ionized b-cyclodextrin on the
nitrosation of amines by phenylpropyl nitrites
Emilia Iglesias
Departamento de Qu•mica F•sica e E. Q. I, Facultad de Ciencias, Universidad de L a Coruna,
15071 L a Coruna, Spain. E-mail: qfemilia=udc.es
Received (in Montpellier, France) 12th July 2000, Accepted 25th September 2000
First published as an Advance Article on the web 23rd November 2000
The inÑuence of b-cyclodextrin (b-CD) on the base-catalyzed hydrolysis reaction of 1-phenyl-1-propyl, 2-phenyl-1-
propyl and 3-phenyl-1-propyl nitrites and on the nitrosation of pyrrolidine, piperidine and
N-methylcyclohexylamine by the aforementioned alkyl nitrites (RONO) is studied in aqueous bu†ers of the amines
and in an alkaline medium with [OH~] \ 0.20 M. The hydrolysis reaction is catalyzed by the presence of b-CD
owing to the formation of reactive 1 : 1 inclusion complexes between the alkyl nitrite and the ionized b-CD; the
addition of potential inhibitors, such as dodecyltrimethylammonium bromide monomers, accelerates the reaction
even more. The e†ect is quite signiÐcant in the case of 1-phenyl-1-propyl nitrite and is viewed as a case of allostery.
In the presence of neutral b-CD, the nitrosation by 1-phenyl-1-propyl nitrite, either of pyrrolidine or piperidine, is
inhibited by b-CD addition; however, the nitrosation reaction of piperidine by 2-phenyl-1-propyl nitrite is
catalyzed (passing through a maximum) by b-CD, whereas the nitrosation of pyrrolidine promoted by 3-phenyl-1-
propyl nitrite exhibits practically no change upon b-CD addition. In alkaline media (containing ionized b-CD) the
nitrosation of pyrrolidine by 1-phenyl-1-propyl nitrite is inhibited by the presence of b-CD; in contrast, the
nitrosation of both piperidine and N-methylcyclohexylamine is catalyzed in all cases, but the degree of catalysis
depends not only on the alkyl nitrite structure, but also on the type and concentration of the amine. Kinetic results
are quantitatively interpreted on the basis of the proposed reaction mechanism in each case, and the kinetic rate
constants of the di†erent steps are determined. Comparison of the results obtained in aqueous alkaline media and
in aqueous bu†ers of the amines themselves allows us to establish important characteristics of the transition state of
the reaction.
Cyclodextrins (CDs) constitute a very popular family of
molecular hosts, capable of forming inclusion complexes, even
in aqueous solutions, with a wide range of low molecular
weight compounds, which are included into the CD cavi-
ties.1h3 Regardless of the stabilizing force involved, geometric
factors (size selectivity) and the hydrophobicity of the guest
molecules are decisive in determining the complex formation
in a considered medium. The process of forming inclusion
complexes is that of a dynamic equilibrium and in general can
be detected directly because both physical (absorption of
light,4 Ñuorescence,5 NMR spectra,6 etc.) and/or chemical7
properties of the guest are modiÐed. The stability of the inclu-
sion complex can be described in terms of the formation equi-
librium constant.
RONO, which transfer the nitroso group (ÈN2O) intact. Both
the acid and base catalyzed hydrolyses of alkyl nitrites take
place through concerted mechanisms;11,12 whereas the hydro-
lysis of esters proceeds via an addition-elimination pathway13
in which the direct participation of a water molecule is
Over the last few years, numerous studies have been cen-
tered on the inÑuence of cyclodextrins on the basic hydrolysis
of carboxylic esters. The cleavage of aryl esters in basic
aqueous solutions is accelerated by the presence of cyclo-
dextrins.8h10 The chemistry of carboxylic esters is often com-
pared with the chemistry of alkyl nitrites (RONO).
SpeciÐcally, while the acid catalyzed hydrolysis of alkyl
nitrites is a very fast process,11 the base catalyzed hydrolysis is
a very slow one;12 however, the contrary applies in the case of
carboxylic esters, which hydrolyze faster in alkaline conditions
than in acidic media.13 This di†erent behavior can be
understood in light of the Lewis molecular structure for both
families of compounds as shown in Scheme 1. The lone pair
on the N atom, along with the higher electronegativity of N
vs. C, explains not only why RONO have higher reactivity
than carboxylic esters towards electrophiles, but also the dif-
ference in the chemistry of carboxylic esters, dominated by the
formation of tetrahedral intermediates, and in the chemistry of
Scheme 1 (a) Mechanism of hydrolysis of alkyl nitrates. (b) Mecha-
nism of hydrolysis of carboxylic esters.
DOI: 10.1039/b005647m
New J. Chem., 2000, 24, 1025È1035
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This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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required: in acid hydrolysis, the water molecule provides the
OH~ ion and thus acts as a base, while in basic hydrolysis,
the water molecule provides a H` and acts as an acid.
We recently reported the formation of 1 : 1 inclusion com-
plexes between b-cyclodextrin (b-CD) and alkyl nitrites in
aqueous media.14,15 As a consequence, the acid hydrolysis of
alkyl nitrites is strongly inhibited by the presence of b-CD.
The lower reactivity, or nonreactivity, of the complexed alkyl
1
Reaction in the absence of b-cyclodextrin
The NO transfer from alkyl nitrites in basic media is a much
slower process than that which occurs in acid media. Never-
theless, NO transfer to an N-nucleophile, such as a secondary
amine, can be a fast process, depending on the amine nucleo-
philicity.21 The reaction between an alkyl nitrite and second-
ary amines in basic media yields stable N-nitrosamines; some
of which are potential carcinogens. The reaction takes place
through a concerted mechanism in which the NO group is
transferred directly to an unprotonated amine molecule.
Fig. 1(a) shows the results obtained for the nitrosation of
PyR, PiP and MCH by 3P1P nitrite, in a basic medium
([OH~] \ 0.20 M). For comparative purposes, Fig. 1(b)
shows the plot of the observed rate constants obtained in the
nitrosation of piperidine by the three alkyl nitrites considered
in this study. The observed rate constant k (\k [OH~]
nitrite was attributed to the restricted access of the H O` to
3
the b-CD cavity since the inclusion of simple cations appears
to be relatively unfavorable, except for large organic dyes,16
long-chain surfactants17 or metal ions with organic ligands.18
On the other hand, the basic hydrolysis of alkyl nitrites is
strongly catalyzed by ionized b-CD. As the pK of b-CD is
a
12.3,19 working in an alkaline medium with [OH~] \ 0.20 M
leads to all the b-CD molecules having an ionized secondary
ÈOH group. The stability of the inclusion complex formed
between ionized b-CD (CD~) and an alkyl nitrite proves to be
lower than the complex formed with the neutral b-CD and in
some cases the di†erences are quite important.15 Catalysis in
alkaline conditions occurs because the complex is the tran-
sition state of the hydrolysis reaction; that is the nucleophilic
catalysis of the bimolecular process RONO ] OH~ becomes
an intramolecular catalysis of the reaction through the
complex RONO É CD~. In the present article, we report the
results of kinetic studies of the b-CD mediated reactions of
1-phenyl-1-propyl (1P1P), 2-phenyl-1-propyl (2P1P) and 3-
phenyl-1-propyl (3P1P) nitrites with OH~ and with pyrroli-
dine (PyR), piperidine (PiP) and N-methylcyclohexylamine
(MCH) in basic media. The work was conceived as a compa-
rative study of the results obtained with three guests of closely
related structures in order to gain a better understanding of
the inclusion process and the catalytic e†ect.
o
OH
] kw [amine]) increases linearly with the amine concentra-
tion, and, in the case of PyR, the intercept at the origin
appears to be negligible; that is the reaction proceeds only up
to the formation of N-nitrosopyrrolidine where the competi-
tive reaction of the base catalyzed hydrolysis of RONO is
insigniÐcant (Scheme 2).
2
Scheme 2
For a given amine [see the case of PiP in Fig. 1(b)], the
secondary alkyl nitrite 1P1P proves to be much more reactive
Experimental
1P1P, 2P1P and 3P1P nitrites were synthesized by treating
the corresponding alcohols with sodium nitrite in aqueous
sulfuric acid;20 they were puriÐed by fractional distillation
and stored at low temperature over 3 A molecular sieves to
prevent their hydrolysis. b-CD was purchased from Aldrich
Co. and was used without further puriÐcation. All other
reagents were supplied by Merck and were used as received.
All solutions were prepared with doubly distilled water
obtained from a permanganate solution.
Kinetic experiments were monitored by using a KontronÈ
Uvikon (model 941) UV-VIS double beam spectrophotometer,
provided with a multiple cell carrier thermostatted by circulat-
ing water. The consumption of alkyl nitrites was observed by
recording decreasing absorbance in the 245È250 nm region.
The kinetics of the nitrosation reaction of amines were studied
by recording the increase in absorbance due to the formation
of N-nitrosoamine (also in the 245È250 nm region). All experi-
ments were performed at 25 ¡C.
Stock solutions of the alkyl nitrites were prepared in
dioxane. Reactions were initiated by the addition of 20 lL of a
solution of alkyl nitrite in dioxane to the rest of the reaction
mixture. The percentage of dioxane in the Ðnal reaction
mixture was less than 1% by volume. The concentration of
alkyl nitrite used was 1È4 ] 10~4 M. Kinetic experiments
were carried out under pseudo-Ðrst-order conditions, with the
OH~ (or amine) concentration at least 50 times greater than
that of the alkyl nitrite. For every case, the integrated method
was followed, Ðtting the experimental absorbance-time data
with the Ðrst-order integrated equation and obtaining satisfac-
tory correlation coefficients ([0.999) and residuals. In what
Fig. 1 (a) InÑuence of the amine concentration on the observed rate
constant of the nitrosation by 3-phenyl-1-propylnitrite of pyrrolidine
(PyR), piperidine (PiP), and N-methylcyclohexylamine (MCH) at
[OH~] \ 0.20 M. (b) Variation of the observed rate constant as a
function of [PiP] in the nitrosation of PiP by 3-phenyl-1-propyl
(3P1P), 2-phenyl-1-propyl (2P1P), and 1-phenyl-1-propyl (1P1P)
nitrites in aqueous alkaline solutions of [OH~] \ 0.20 M.
follows, k denotes the observed pseudo-Ðrst-order rate con-
o
stant, the values which were usually reproducible to within
2%.
1026
New J. Chem., 2000, 24, 1025È1035

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than the primary alkyl nitrite 3P1P. In general, reactivity is
related to the stability of the leaving alkoxide in the rate con-
trolling step. One would expect the leaving alkoxide to be
strongly hydrogen-bonded to the solvent, and this strong sol-
vation accounts for the highly negative value of the activation
entropy.21 Therefore, the more electronegative the R substit-
uent (ROÈNO), or the greater the stabilization (e.g. by the
resonance e†ect) of the negative charge on the O atom, the
faster the nitrosation reaction.
complex. Therefore, using Scheme 3 and taking into account
that [RONO] @ [b-CD], we obtain eqn. (1) to relate values of
k to [b-CD].
o
k
[OH~] ] k K [b-CD]
OH
c c
k \
(1)
o
1 ] K [b-CD]
c
Solid lines in Fig. 2 (solid points) correspond to the theoretical
Ðt of eqn. (1) to the experimental points. The resulting param-
eters of k (\kw/[OH~]), k and K are listed in Table 2,
Table 1 reports the experimental results along with values
of kw/k , which gives the ratio [nitrosamine]/[NO ~] that
OH
o
c
c
along with values of k (\k K ), that is, the second-order rate
2
c
c
2
OH
2
constant for the reaction RONO ] CD~ ] products, which
measures the ability of CD to select among di†erent RONO
one would expect to obtain in a reaction mixture of equal
amine and OH~ concentrations. In each trial, this ratio is
favorable to nitrosamine formation; nevertheless, as the
[OH~] used here is always higher than the [amine] (from 13-
to 120-fold), the hydrolysis process must be taken into
account, mainly in those experiments carried out at low amine
concentrations.
under nonsaturating conditions. The highest k value is
2
observed with 2P1P nitrite and the smallest one with 1P1P
nitrite. This Ðnding illustrates the importance of the guest
geometry in a†ecting the host in the reactivity of the complex.
2P1P possesses the most suitable structure for residing in the
b-CD cavity in such a way that the reactive centers (ÈN2O in
the alkyl nitrite and ÈO~ in the b-CD) closely approach each
other in a favorable conÐguration. Branching substituents
attached to the C atom attached to the ÈNO group make the
reaction difficult due to steric hindrance.
2
Reactions in the presence of b-CD
(A) Hydrolysis reaction
Alkaline hydrolysis of alkyl nitrites is an extremely slow
process when no harsh conditions are used, such as moderate
[OH~]. The addition of b-CD strongly enhances the rate of
the hydrolysis reaction. The degree of catalysis depends on the
alkyl nitrite structure. Fig. 2(a) (solid points) shows the varia-
tion of the observed rate constant k obtained in the cleavage
o
of 2P1P and 1P1P nitrites at [OH~] \ 0.20 M, as a function
of b-CD concentration. The primary alkyl nitrite 2P1P experi-
ences the largest catalytic e†ect (data for 3P1P not shown).
Scheme 3
Kinetic experimental proÐles of k vs. [b-CD] are explained
o
quantitatively by considering the formation of reactive inclu-
sion complexes between ionized b-CD molecules (CD~) and
the alkyl nitrite. The presence of saturation kinetics in every
case is indicative of a 1 : 1 stoichiometry for the inclusion
The e†ect of DTABr. The catalysis observed with 1P1P
nitrite is strongly magniÐed if the reaction is carried out in the
presence of a Ðxed amount of dodecyltrimethylammonium
Table 1 Experimental conditions and bimolecular rate constants obtained in the basic hydrolysis (k ) and in the nitrosation of amines (kw) by
OH
2
phenylpropyl nitrites in an aqueous alkaline medium with [OH~] \ 0.20 M
RONO
Amine
[Amine]a/10~3 M
kwb/10~4 s~1
kw/dm3 mol~1 s~1
kw/k
OH
o
2
2
1P1P
1P1P
1P1P
2P1P
2P1P
2P1P
3P1P
3P1P
3P1P
PyR
PiP
MCH
PyR
PiP
MCH
PyR
PiP
1.5È13
1.6È13
1.5È12
1.0È13
1.5È13
1.5È15
1.5È13
1.5È13
1.5È13
0.61 ^ 0.35
0.8 ^ 0.1
1.073 ^ 0.005
0.193 ^ 0.002
0.092 ^ 0.001
0.691 ^ 0.007
0.124 ^ 0.002
0.055 ^ 0.001
0.298 ^ 0.006
0.0485 ^ 0.001
0.0283 ^ 0.0008
3100
550
260
2000
350
100
1200
190
110
0.75 ^ 0.06
0.65 ^ 0.20
0.80 ^ 0.12
1.15 ^ 0.09
0.83 ^ 0.66
0.50 ^ 0.03
0.48 ^ 0.06
MCH
a Range of [amine]. b kw \ k [OH~].
OH
o
Table 2 Parameters obtained in the study of the inÑuence of b-CD concentration on the basic hydrolysis of phenylpropyl nitrites in an aqueous
alkaline medium ([OH~] \ 0.20 M) at 25 ¡C by Ðtting the experimental data to eqn. (1)
RONO
[DTABr]a/10~3 M
k
/10~4 dm3 mol~1 s~1
k /10~3 s~1
K /dm3 mol~1
k /dm3 mol~1 s~1
OH
c
c
2
3P1P
2P1P
2P2Pb
1P1P
1P1P
1P1P
1P1P
1P1P
È
È
È
0.0
3.4
5.1
6.8
10.2
2.8
3.5
Too slow
3.25
3.25
3.25
2.45 ^ 0.05
3.43 ^ 0.07
No e†ect
0.72 ^ 0.02
1.37 ^ 0.04
1.69 ^ 0.04
2.17 ^ 0.06
2.78 ^ 0.08
315 ^ 10
265 ^ 13
È
279 ^ 22
295 ^ 25c
246 ^ 13c
179 ^ 11c
137 ^ 7c
0.77
0.91
È
0.20
0.40
0.41
0.39
0.38
3.25
3.25
a Concentration of dodecyltrimethylammonium bromide. b Ref. 15. c Kap.
c
New J. Chem., 2000, 24, 1025È1035
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lower than [DTABr], one can explain the present results only
by considering
a case of allostery by analogy with
enzymes.25,26 In this sense, DTABr monomers may be seen as
modiÐers or as e†ectors that inÑuence the catalytic efficiency of
b-CD by inducing conformational changes or a more proper
disposition of the guest, thus altering the reactivity of the
complex. In fact, k increases linearly with DTABr concentra-
c
tion, being 4 times the value corresponding to the unmodiÐed
reaction (no added DTABr) at 0.01 M of DTABr monomer
(the maximum monomer concentration possible); but k , the
2
second-order rate constant for the reaction of complexed
1P1P with the host (ionized b-CD), doubles its value in the
presence of a small amount of DTABr. This means a
reduction of 1.5 kJ mol~1 in the activation energy of the reac-
tion.
Since urea is an important protein denaturing agent, we
also analyzed the inÑuence of urea on the basic hydrolysis of
1P1P carried out in the presence of b-CD. We found no e†ect
on reactivity, even at 3.0 M urea. Previous related results indi-
cated that the presence of 7 M urea decreases the binding con-
stant of p-toluidinonaphthalene sulphonate27 to a-CD from
120 to 55 dm3 mol~1, and to b-CD, from 2200 to 95 dm3
mol~1. In contrast, the presence of 8 M urea increases the
binding constant of 2-naphthoate anion28 to b-CD from 320
to 3990 dm3 mol~1; thus, the observed e†ect seems to depend
on the guest.
(B) Reaction with amines
Self-bu†ered solution of the amine. Nitrosation of pyrroli-
dine. The nitrosation of PyR by 3P1P and 1P1P nitrites under
conditions of neutral b-CD, that is in aqueous bu†ered solu-
tions of pyrrolidineÈpyrrolidinium chloride of pH 11.20 and
[PyR] \ 0.020 M, has been studied. The observed rate con-
Fig. 2 (a) Variation of k as a function of [b-CD] in the basic hydro-
t
o
stants k are displayed in Fig. 3 as a function of [b-CD].
lysis ([OH~] \ 0.20 M) of 2P1P (…) and 1P1P nitrite (>) and of
o
o
While k appears to be unchanged by the presence of b-CD in
1P1P in the presence of di†erent concentrations of DTABr monomer
the nitrosation by 3P1P nitrite, the reaction with 1P1P proves
()) 3.4, (È) 5.1, (|) 6.8 and (L) 10.2 mM. (b) Variation of k as a
o
function of [DTABr] in the basic hydrolysis of 1P1P at [b-CD] of
to be strongly inhibited by increasing amounts of b-CD. The
di†erence in behavior between 3P1P and 1P1P nitrites could
be explained if the former did not enter into the b-CD cavity,
but this possibility must be ruled out because the acid hydro-
lysis of both alkyl nitrites is strongly inhibited by b-CD, from
which experiments we determined the corresponding stability
(…) 7.38 and (>) 3.7 mM.
bromide (DTABr). Fig. 2(a) (open points) shows the variation
of k as a function of [b-CD] in the presence of Ðxed DTABr
o
concentrations below the CMC (critical micelle concentra-
tion: for this surfactant, CMC \ 12 mM).22 As one can see,
the e†ect is greater if one increases both the b-CD and
DTABr monomer concentrations. This behavior is better rep-
resented in Fig. 2(b), which shows the inÑuence of [DTABr]
constants for complex formation: KN \ 350 dm3 mol~1 for
c
3P1P and KN \ 590 dm3 mol~1 for 1P1P.15 (Notice that
c
these equilibrium constants for complex formation between
the alkyl nitrite and neutral b-CD are higher than those
on k at Ðxed [b-CD], and at surfactant concentrations below
corresponding to the inclusion into the ionized b-CD, K ; see
o
c
and above the CMC. Once micelles of DTABr are formed
Table 2.)
(above the CMC), the system becomes more complicated; the
net observed e†ect represents an inhibition of the reaction
because of the solubilization of the alkyl nitrite into the micel-
les, a process that favors the uncatalyzed reaction, which is
much slower than the reaction mediated by b-CD.
A reasonable explanation could be due to the possibility of
H-bonding between RONO and C-2 or C-3 secondary ÈOH
groups of neutral b-CD: RÈO(NO)É É ÉHÈOÈ, which is impossi-
ble with ionized b-CD.7c On the other hand, neutral PyR
binds to b-CD very slightly; the stability constant for the
complex formation was estimated as 6 dm3 mol~1.14 There-
fore, we can expect that neutral PyR would locate closely to
the ÈOH groups on the wide rim of the b-CD molecule, inter-
acting by H-bonding with these groups. Protonated hydro-
philic amines are not seen to include into the hydrophobic
b-CD cavity.29 Following these considerations, the lack of
inÑuence of b-CD in the reaction of PyR ] 3P1P could be
understood if there were no remarkable di†erence between the
reactivity of free and complexed 3P1P nitrites toward PyR. By
In acidic media, DTABr monomers compete with the alkyl
nitrite for the b-CD cavity by expelling the included RONO
molecules.14,15 If the same e†ect were to occur here, the addi-
tion of DTABr monomers would result in inhibition of the
reaction because the RONO É CD~ complex is more reactive
than free RONO. Nevertheless, the contrary is observed:
addition of DTABr strongly catalyzes the basic hydrolysis of
1P1P. By Ðtting the experimental results obtained under these
conditions to eqn. (1), the curves in Fig. 2(a) are drawn, and
the obtained values of k and Kap are also reported in Table 2.
considering the concentrations of both PyR (i.e. [PyR] \
c
c
t
Kap values decrease slightly on increasing the concentration of
[PyR]) and b-CD forming complexes (because [RONO] @
c
DTABr monomers, while k increases strongly with [DTABr].
The stability constant for the complex formation between
[b-CD], then [b-CD] \ [b-CD]) to be negligible, one arrives
c
t
at eqn. (2) from Scheme 4, put forward for the case of 1P1P.
b-CD and dodecyltrimethylammonium monomers is reported
kw ] kc KN[b-CD]
in the literature23,24 as 3000 dm3 mol~1. Comparing this
2
2 c
k \
[PyR]
(2)
o
n
value with K values and taking into account that [RONO] is
1 ] KN[b-CD]
c
c
1028
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In eqn. (2), [PyR] refers to the unprotonated PyR, which was
n
determined as K [PyR] /(K ] [H`]), with K being the
a
t
a
a
acidity constant of pyrrolidinium cation (pK \ 11.40)30,31
a
and with kw being the rate constant for the bimolecular reac-
2
tion in water determined in the preceding section. Also shown
in Fig. 3 is the plot of kcor M\k (1 ] KN[b-CD])N vs. [b-CD],
o
o
c
resulting in a straight line, in agreement with eqn. (2). The
linear regression analysis of the data gives values of
(2.29 ^ 0.07) and (7.75 ^ 0.09) ] 10~3 s~1 for the intercepts
(\kw[PyR] ) and values of 0.66 ^ 0.02 and 0.27 ^ 0.03 dm3
2
n
mol~1 s~1 for the corresponding slopes (\kcKN[PyR] ) of
2
c
n
the plots obtained in the nitrosation of PyR by 3P1P and
1P1P nitrites, respectively. [In the case of 1P1P, the experi-
mental data were also Ðtted to eqn. (2) by using a non-linear
regression analysis. The values determined for the unknown
parameters are independent of the Ðtting method].
Using these results, along with the values of [PyR] and
n
KN, one obtains the kw and kc values displayed in Table 3.
c
2
2
The values of kw compare quite well with those in Table 1,
which were found by studying the reaction in the absence of
2
b-CD. But the most striking feature of these results are the
similar values determined for kw and kc in the case of 3P1P;
2
2
the reactivity of this alkyl nitrite, free or complexed to b-CD,
is practically the same. In contrast, the complexed 1P1P is
more than 20-fold less reactive than free 1P1P nitrite. The
explanation for this Ðnding can be arrived at by looking at the
structure and dimensions of a molecule of both alkyl nitrites
in comparison to the size of the b-CD cavity: while the NO
group in 3P1P must lie completely outside the b-CD cavity,
which results in no di†erence in its reactivity, the same group
in the case of 1P1P lies completely inside the b-CD cavity (see
Scheme 5). Thus, the restricted access of PyR molecules to the
b-CD interior, together with the low polarity of this micro-
environment, makes the reaction slower than it is in water.
Nitrosation of piperidine. We also tested the reaction of
Fig. 3 Values of (…) k and (>) kcor M\k (1 ] KN[b-CD])N as a func-
o
o
o
c
tion of [b-CD] obtained in the nitrosation of PyR by (a) 1P1P and (b)
3P1P in a bu†er of pyrrolidineÈpyrrolidinium chloride of pH 11.20
1P1P and 2P1P with PiP in
a bu†er of piperidineÈ
and [PyR] \ 0.020 M. Solid lines Ðt eqn. (2); for parameters, see
t
piperidinium chloride of pH 11.02 and [PiP] \ 0.020 or 0.033
Table 3.
t
M. The experimental results are shown in Fig. 4. The addition
of b-CD strongly inhibits the nitrosation of PiP by 1P1P, but
the observed pseudo-Ðrst order rate constant k goes through
o
a maximum when the nitrosation is e†ectivated by 2P1P
nitrite. Unlike PyR, neutral piperidine forms inclusion com-
plexes with b-CD; the equilibrium constant for the complex
stability has been reported29 as KA \ 50 dm3 mol~1. Under
c
the above experimental conditions, the neutral piperidine con-
centration is [PiP] M\K [PiP] /(K ] [H`])N \ 7.15 ] 10~3
n
a
t
a
or 0.0124 M (with K being the acidity constant of piperidin-
a
ium ion, pK \ 11.24).30,31 We must consider here the
a
amount of b-CD forming complexes with neutral PiP, since
both concentrations are comparable. (It should be noted that
we do not consider the total PiP concentration, due to the
Scheme 4
Table 3 Experimental conditions and rate constants obtained in the kinetic study of the inÑuence of [b-CD] in the nitrosation of pyrrolidine
and piperidine by phenyl-1-propyl nitrites in aqueous self-bu†ered solutions of the amine at pH 11.20 (for PyR) and pH 11.02 (for PiP)
kw/
kc or kc{b/
2
2
2
RONO
Amine
[Amine] /M
KN/dm3 mol~1
Xa/dm3 mol~1 s~1
kw/10~3 s~1
dm3 mol~1 s~1
dm3 mol~1 s~1
t
c
o
3P1P
1P1P
PyR
PyR
0.020
0.020
355c
590c
0.66 ^ 0.02
0.27 ^ 0.03
2.29 ^ 0.07
7.75 ^ 0.09
0.296
1.03
0.243
0.045
(0.059)
0.029
(0.033)
0.218
(0.216)
0.195
528 ^ 15d
1P1P
2P1P
2P1P
PiP
PiP
PiP
0.020
0.020
0.033
590c
0.145 ^ 0.013
0.75 ^ 0.05
1.26 ^ 0.07
1.49 ^ 0.02
0.93 ^ 0.02
1.82 ^ 0.05
0.207
0.129
0.144
582 ^ 14d
406c
430 ^ 34d
406c
435 ^ 30d
(0.204)
a X \ kc KN[PyR] or (kc KN ] kc{KA)[PiP] . b Values obtained from the linear plot of kcor vs. [CD] (or from the nonlinear regression analysis of
2
c
n
2
c
2
c
n
o
k vs. [CD]). c Determined in the acid hydrolysis15 and used to draw the linear plots of kcor vs. free [b-CD]. d Obtained by Ðtting k vs. [b-CD],
o
o
o
eqn. (2) (PyR) or eqn. (4) (PiP) with KA \ 50 dm3 mol~1.
c
New J. Chem., 2000, 24, 1025È1035
1029

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Scheme 5
negligible binding of piperidinium cations with b-CD). Taking
system PiP ] 1P1P, kc should be much smaller than kw in
2
2
into account the mass balance equations [b-CD] \ [CD]
order to be able to explain the strong inhibition. To determine
t
] b-CD É PiP] and [PiP] \ [PiP] ] [b-CD É PiP] and
n
kc and kc{, a reasonable assumption may be that both con-
2
2
Scheme 6, one arrives at eqn. (3) to determine the free b-CD
stants are equal; thus, the site of the reaction should not be
concentration ([CD]).
very di†erent. We then obtain the rate constants kc (or kc{)
2
2
reported in Table 3. As expected, the reaction between com-
plexed 1P1P (or PiP) and free PiP (or 1P1P) is nearly 7-fold
slower than the reaction between free reagents; in contrast,
the complexed 2P1P (or PiP) is nearly 2-fold more reactive
towards free PiP (or 2P1P) than the free reagents. Possible
reasons for these results are: Ðrstly, the di†erent behavior of
the alkyl nitrites is a consequence of their structures, and sec-
ondly, the lower polarity and hydration of the reaction site,
along with the restricted access of PiP molecules to the N
atom of 1P1P included inside the b-CD cavity, explain the
lower reactivity that results in the observed inhibition.
However, we will present the results of the next section before
further discussing this point.
1
[b-CD]
t
\ 0 (3)
[CD]2 ] [CD]([PiP] ]
[ [b-CD] ) [
n
t
KA
KA
c
c
By solving this second-order equation at each experimental
[b-CD], one may calculate the free CD concentration, [CD].
Fitting the experimental data to eqn. (4) by using KA \ 50
c
dm3 mol~1 provides the results given in Table 3.
kw ] (kc KN ] kc{KA)[CD]
2
2
c
2 c
k \
[PiP]
(4)
o
n
(1 ] KN[CD])(1 ] KA[CD])
c
c
The values of kw obtained from those of kw (\kw[PiP] )
2
o
2
n
agree perfectly with those in Table 1. In addition, the KN
c
values determined in this section, in aqueous bu†ered solu-
tions of the amines at pH ca. 11, compare quite well with
those determined in the study of the acid hydrolysis (aqueous
solutions of acetic acidÈacetate bu†er of pH ca. 5). In Fig. 4 it
is also evident that kcor M\k (1 ] KN[CD]) É (1 ] KA[CD])N
increases linearly with [CD] when the nitrosation is carried
out either by 1P1P or by 2P1P nitrites. This behavior is evi-
dence that there is no reaction between the two complexed
reactants (vide infra) and that the rate constants corresponding
Nitrosation in alkaline solution. The inÑuence of [b-CD] on
the nitrosation of PyR, PiP, and MCH by phenylpropyl
nitrites was also studied in an alkaline aqueous medium with
[OH~] \ 0.20 M, that is under conditions where the majority
of the b-CD molecules possesses an ionized secondary ÈOH
group.
Reaction with pyrrolidine. The kinetic results obtained for
the reaction of PyR with 1P1P and 3P1P nitrites are dis-
played in Fig. 5. In the case of 1P1P, the pseudo-Ðrst order
rate constant decreases as [b-CD] increases, but the opposite
occurs with 3P1P, with simple saturation kinetics resulting in
o
o
c
c
to either the reaction between PiP and complexed RONO (kc)
2
or between free RONO and complexed PiP (kc{) should be
2
comparable to the rate constant of the reaction between free
reagents (kw). Nevertheless, with 2P1P the bimolecular rate
2
constant kc (or its kinetically equivalent kc{) should be slightly
both cases. The experimental behavior of k vs. [b-CD]
2
2
o
higher than kw to be able to explain the smooth increase of k
obtained with 2P1P resembles that obtained with 3P1P,
2
o
at low [b-CD], that is when the concentration of PiP É CD is
not signiÐcant, but at higher [b-CD], when the complexed
catalysis is observed. Nevertheless, the degree of catalysis (or
inhibition, in the case of 1P1P) depends on the molecular
structure of the alkyl nitrite. Table 4 (3rd column) shows the
values of the observed rate constants obtained at the
maximum [b-CD] used (ca. 0.010 M), kmax. The ratio kmax/kw
[PiP] becomes important, k decreases. In contrast, in the
o
o
o
o
is indicative of the degree of catalysis (or inhibition). One may
verify that kmax/kw decreases as [PyR] increases for the cases
o
o
of 2P1P and 3P1P, and at constant [amine] the ratio is higher
with 3P1P than with 2P1P. The contrary applies to the case
of 1P1P: the strongest inhibition e†ect is observed at
[PyR] \ 0.010 M and is practically negligible (no e†ect of
b-CD addition) at [PyR] \ 1.5 ] 10~3 M.
Remembering that the stability constant of the inclusion
complex formed between PyR and neutral b-CD has been
estimated as KA \ 6 dm3 mol~1, and even working at
c
[PyR] \ 0.015 M (the maximum concentration used), one will
Ðnd that the amount of amine forming inclusion complexes
will be insigniÐcant; nevertheless, we have to consider the
Scheme 6
1030
New J. Chem., 2000, 24, 1025È1035

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tion. On the basis of these considerations, eqn. (5) is deduced
when one recalls that the rate of disappearance of RONO is
the sum of the rate of the three steps (hydrolysis of complexed
RONO, k , and nitrosation of PyR by free, kw , and complex-
c
2
ed, kc RONO).
2
kw ] aK [b-CD]
o
c
k \
(5)
o
1 ] K [b-CD]
c
with a \ k ] kc[PyR] and kw \ kw[PyR].
c
2
o
2
When we Ðt the experimental data with eqn. (5), by using
nonlinear regression analysis, we obtain the values of a and
K reported in Table 4, by using the known values of kw listed
c
o
in the table. Solid lines in Fig. 5 correspond to the theoretical
Ðt of the model to the experimental points. On the other hand,
as eqn. (5) indicates, the graph of kcor M\k (1 ] K [b-CD])N
o
o
c
against [b-CD] should result in straight lines. To draw these
plots, we used the K values determined from the basic hydro-
c
lysis, K \ 265 or 300 dm3 mol~1 for 1P1P and 3P1P, respec-
tively. As is shown in Fig. 6, the observed experimental
c
behavior is in accordance with eqn. (5). In addition, the values
of a determined at each [PyR] (either from the slope of the
linear plots or from the nonlinear regression analysis) should
increase proportionally to [PyR]. This is indeed the experi-
mental behavior observed. (Plots are not shown; instead, we
report kc values determined at each aÈ[PyR] pair.)
2
Viewing the results obtained, we must comment on the fol-
lowing. The rate constant of the reaction of complexed 2P1P
(or 3P1P) with PyR, kc, is practically equal to kw, that is com-
2
2
plexed alkyl nitrites react at the same rate as free RONO. The
Fig. 4 (a) Values of (…) k and (>) kcor M\k (1 ] KN[b-CD])(1
o
o
o
c
] KA[b-CD])N obtained in the nitrosation of PiP by 1P1P in a bu†er
c
of piperidineÈpiperidinium chloride of pH 11.02 and [PiP] \ 0.020
t
M as a function of [b-CD] and (@) of free [b-CD]. Variation of (b) k ,
o
the pseudo-Ðrst order rate constant and of (c) kcor obtained in the
o
nitrosation of PiP by 2P1P in a bu†er of piperidineÈpiperidinium
chloride of pH 11.02 and [PiP] \ (>) 0.020 or (…) 0.033 M as a
5
function of free [b-CD]. Solid lines are Ðts from eqn. (4), for param-
eters, see Table 3.
inclusion into the ionized b-CD of the alkyl nitrites studied
here, whose equilibrium constants for complex formation are
around 300 dm3 mol~1 (see Table 2). In the presence of OH~
the basic hydrolysis reaction via free (k ) or complexed (k )
OH
c
RONO must be taken into account, along with the nitro-
Fig. 5 Variation the observed rate constant k as a function of b-CD
sation process of PyR through free RONO (kw) and the
o
2
RONO É CD~ complex (kc). As we have shown in our study of
2
concentration obtained in the nitrosation in an alkaline medium
([OH~] \ 0.20 M) of pyrrolidine by (a) 1-phenyl-1-propyl nitrite at
[PyR] equal to (…) 1.6, (>) 3.2, (@) 6.4 and (+) 10 mM; and by (b)
3-phenyl-1-propyl nitrite at [PyR] of (…) 1.6, (>) 3.2, (@) 6.4 and (+)
12.8 mM. Solid lines are Ðts to eqn. (5); for parameters, see Table 4.
the reaction in water, the reaction rate of the nitrosation
process is much higher than that corresponding to the basic
hydrolysis, which results in a simpliÐcation of the rate equa-
New J. Chem., 2000, 24, 1025È1035
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Table 4 Experimental conditions used in the nitrosation of pyrrolidine in an aqueous alkaline medium ([OH~] \ 0.20 M) by 1P1P, 2P1P and
3P1P nitrites performed in the presence of b-CD and parameters obtained by Ðtting the experimental data to eqn. (5)
[PyR]/10~3 M
kw/10~3 s~1
kmaxa/10~3 s~1
a/10~3 s~1
K /dm3 mol~1
kw/dm3 mol~1 s~1
k /10~3 s~1
kc/dm3 mol~1 s~1
o
o
c
2
c
2
1P1P
1.5
3.2
6.4
10
2P1P
1.6
3.2
3P1P
1.6
3.2
1.51
3.54
7.35
11.2
1.41
2.42
3.89
5.63
1.3 ^ 0.2
1.93 ^ 0.03
2.52 ^ 0.05
3.81 ^ 0.04
270 ^ 30
272 ^ 13
268 ^ 9
264 ^ 9
1.03
1.11
1.16
1.12
0.72
0.72
0.72
0.72
0.387
0.378
0.281
0.309
1.04
1.96
3.41
4.6
4.39 ^ 0.05
5.69 ^ 0.06
254 ^ 12
263 ^ 8
0.65
0.61
3.43
3.43
0.619
0.707
0.42
0.85
1.8
4.01
4.07
5.74
6.60
4.65 ^ 0.09
5.14 ^ 0.20
6.18 ^ 0.08
7.68 ^ 0.08
315 ^ 14
303 ^ 32
295 ^ 13
288 ^ 15
0.237
0.267
0.281
0.275
4.2
4.2
4.2
4.2
0.281
0.294
0.309
0.272
6.4
12.8
3.52
a Value of k obtained at the highest b-CD concentration used (ca. 0.010 M).
o
same observation may be seen when 3P1P and neutral b-CD
are used (see Table 3). In contrast, with 1P1P (a secondary
alkyl nitrite) the reaction between the complex 1P1P É CD and
PyR is nearly 3-fold slower than the reaction of PyR with free
1P1P, although the inhibition has greater importance when
b-CD is not ionized because reaction in the CD anion is 7
the important association of these alkyl nitrites to b-CD
makes the hydrolysis process more noticeable.
Piperidine and N-methylcyclohexylamine. Typical results
obtained in the nitrosation of PiP by 2P1P and of MCH by
3P1P at [OH~] \ 0.20 M in the presence of b-CD are shown
in Fig. 7(a) and 8 (insert), respectively. In every case a catalytic
e†ect was observed with increasing amounts of b-CD. These
amines are less reactive than PyR and more hydrophobic, in
the sense that the stability constants of the corresponding
inclusion complexes with b-CD are much higher than that
with PyR: KA \ 50 dm3 mol~1 for PiP29 and KA \ 550 dm3
times faster that in the neutral form: kc(ionized) B
2
7kc(neutral). These results account for the inhibition observed
2
in the reaction of 1P1P ] PyR on addition of b-CD. The
catalysis observed with the other two alkyl nitrites is due to
the hydrolysis of the complex (step k in Scheme 3), whose rate
c
c
c
constant is comparable to the nitrosation rate constant, but
Fig. 7 (a) Variation of k as a function of free b-CD concentration
o
obtained in the nitrosation in an aqueous alkaline medium
Fig. 6 Plot of kcor M\k (1 ] K [b-CD])N against [b-CD] obtained in
([OH~] \ 0.20 M) of piperidine by 2-phenyl-1-propylnitrite at [PiP]
o
o
c
the nitrosation of PyR at several [PyR] with (a) 1-phenyl-1-propyl
of (…) 1.67, (>) 3.3 and (@) 5.0 mM. (b) Plot of kcor M\k (1 ] K [b-
o
o
c
nitrite (K \ 265 dm3 mol~1) and (b) 3-phenyl-1-propyl nitrite (K \
CD] )(1 ] KA[b-CD] )N with K \ 265 dm3 mol~1 and KA \ 50 dm3
c
c
f
c
f
c
c
300 dm3 mol~1). See Fig. 5 caption for the [PyR] values.
mol~1. Solid lines are Ðts to eqn. (6); for parameters see Table 5.
1032
New J. Chem., 2000, 24, 1025È1035

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mol~1 for MCH.32 Therefore, the amount of amine forming
complexes is not negligible, but we may neglect the b-CD con-
centration forming complexes with the alkyl nitrite (due to the
much lower concentration of the latter). From the correspond-
ing mass balance equations, one may devise an equation of
type (3) to ascertain the free [b-CD] at each stoichiometric
value; it must be remembered that in the present experimental
conditions all the amine is in the neutral form. MFor the sake
of comparison, we can see in Fig. 8 the values of k plotted
o
against total b-CD concentration (insert) and against free
[b-CD].N
A reaction mechanism is proposed here in Scheme 7 for the
case of PiP, in which the following are represented: the basic
hydrolysis reaction via either OH~ (k ) or ionized b-CD (k ),
OH
c
the possibility of nitrosation reactions of free RONO with free
amine (kw), the complexed amine (PiP É CD) with the free
2
2
RONO (kc{), or its kinetically equivalent reaction of the free
amine with the complexed RONO (kc), and the complexed
2
RONO and complexed amine (kcc). The rate of the reaction is
2
the sum of the six reaction steps; but, as with PyR, the reac-
tion via k may be ignored. Taking into account that the
OH
concentrations of the species are given by [RONO] \
t
[RONO] ] [RONO É CD];
[PiP] \ [PiP] ] [PiP É CD],
Scheme 7
] kccK KA[PiP] (or [MCH]) and [CD] represents free b-
t
and [CD] \ [CD] ] [PiP É CD], the expressions of
K
t
c
and KA given in Scheme 7, one arrives easily at eqn. (6),
2
c
c
t
cyclodextrin concentration.
c
where c \ k K ] (kcK ] kc{KA)[PiP] and d \ k K KA
c
c
2
c
2
c
t
c
c
c
kw ] c[CD] ] d[CD]2
o
k \
(6)
o
(1 ] K [CD])(1 ] KA[CD])
c
c
Since kw and the equilibrium constants are known, we can
o
calculate c and d values by a nonlinear regression analysis of
the experimental data k È[b-CD], Ðtted either to eqn. (6) or to
o
its modiÐcation in the form of kcor M\k (1 ] K [CD])(1
o
o
c
] KA[CD])N vs. [CD]. Solid lines in Fig. 7(a) and 8 corre-
spond to the Ðt to eqn. (6) of the experimental k values and
c
o
[CD], and those in Fig. 7(b) correspond to the Ðt of kcor (\kw
o
o
] c[CD] ] d[CD]2) against free [b-CD]. Values of c and d
determined in the nitrosation of PiP are collected in Table 5,
and those corresponding to the nitrosation of MCH are listed
in Table 6, along with the experimental conditions and the
input parameters used in the Ðtting process.
A comparison of the data plotted in Fig. 4 and 7(b), corre-
sponding to the variation of kcor as a function of free [b-CD]
o
obtained in the nitrosation of PiP by 1P1P in a bu†er of the
amine (neutral CD) and by 2P1P in an alkaline medium,
respectively, indicates that the d parameter, for the reaction
via both complexed substrates (RONO and PiP), is important
only in alkaline medium and can be disregarded (the perfect
Fig. 8 Plot of k against free b-CD concentration obtained in the
o
nitrosation in aqueous alkaline medium ([OH~] \ 0.20 M) of N-
methylcyclohexylamine by 3-phenyl-1-propylnitrite at [MCH] of (…)
straight line of kcor vs. free [b-CD]) when b-CD is neutral. In
7.7, (>) 5.4, (@) 3.1 and (+) 1.8 mM. (insert) Plot of k against total
o
o
addition, the plot of c or d (obtained in the nitrosation of
b-CD concentration. Solid lines are Ðts to eqn. (6); for parameters, see
Table 6.
MCH by 3P1P) against the amine concentration gives a per-
Table 5 Parameters obtained in the nitrosation of piperidine in an aqueous alkaline medium ([OH~] \ 0.20 M) by 3P1P, 2P1P and 1P1P
nitrites performed in the presence of b-CD; rate and equilibrium constants obtained by Ðtting the experimental data to eqn. (6)
kw/10~3
c/dm3
d/dm6
K /dm3
c
KA/dm3
c
k /10~3
kw/dm3
2
kc, kc{/dm3
kcc/dm3
2
o
c
2
2
[PiP]/10~3 M
s~1
mol~1 s~1
mol~2 s~1
mol~1
mol~1
s~1
mol~1 s~1
mol~1 s~1
mol~1 s~1
3P1P
1.67
3.30
5.80
2P1P
1.67
3.3
0.133
0.215
0.334
1.04 ^ 0.02
1.16 ^ 0.01
1.26 ^ 0.02
73 ^ 4
99 ^ 2
294 ^ 10
314 ^ 5
318 ^ 8
47 ^ 3
51 ^ 2
55 ^ 3
4.2a
3.1b
3.2c
0.0485
0.0485
0.0485
0.153
0.153
0.153
0.884
0.884
0.884
131 ^ 5
0.28
0.52
0.69
0.89 ^ 0.02
1.02 ^ 0.02
1.21 ^ 0.03
41 ^ 4
62 ^ 4
84 ^ 7
308 ^ 20
278 ^ 15
284 ^ 12
51 ^ 9
51 ^ 3
45.5 ^ 5
3.4a
2.5b
1.4c
0.124
0.124
0.124
0.279
0.279
0.279
0.922
0.922
0.922
5.0
1P1P
1.67
3.3
0.36
0.65
0.21 ^ 0.01
D0.25
14 ^ 1
D16
254 ^ 15
54 ^ 2
0.72a
0.72a
0.193
0.193
0.037
D0.057
0.20
D0.15
265
50
a Obtained in the basic hydrolysis, Table 3. b Obtained from the plot of c vs. [PiP]: c \ k K ] (kc KA ] kc{K )[PiP]. c Obtained from the
c
c
2
c
2 c
intercept of the plot of d vs. [PiP]: d \ k K KA ] kccK KA[PiP].
c
c
c
2
c c
New J. Chem., 2000, 24, 1025È1035
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Table 6 Parameters obtained in the nitrosation of N-methylcyclohexylamine in an aqueous alkaline medium ([OH~] \ 0.20 M) by 3P1P, 2P1P
and 1P1P nitrites performed in the presence of b-CD; rate and equilibrium constants obtained by Ðtting the experimental data to eqn. (6)
kw/10~3
kmax/10~3
c/dm3
d/dm6
K /dm3
c
KA/dm3
c
k /10~3
kc, kc{/dm3
kcc/dm3
2
o
o
c
2
2
[MCH]/10~3 M
s~1
s~1
mol~1 s~1
mol~2 s~1
mol~1
mol~1
s~1
mol~1 s~1
mol~1 s~1
3P1P
1.84
3.07
5.37
7.70
2P1P
1.53
3.07
6.10
7.67
1P1P
3.07
6.13
0.062
0.128
0.199
0.265
2.83
3.35
3.70
3.85
1.79 ^ 0.07
2.21 ^ 0.05
2.98 ^ 0.05
3.62 ^ 0.06
593 ^ 20
651 ^ 12
769 ^ 17
854 ^ 22
307 ^ 8
299 ^ 5
315 ^ 6
320 ^ 15
548 ^ 13
551 ^ 9
2.6a
4.0b
3.0c
È
0.36
0.36
0.36
0.36
0.26
0.26
0.26
0.26
552 ^ 10
580 ^ 45
0.197
0.291
0.459
0.624
1.97
2.59
3.62
3.70
1.29 ^ 0.07
1.87 ^ 0.09
3.32 ^ 0.04
3.86 ^ 0.06
349 ^ 9
273 ^ 12
250 ^ 8
552 ^ 7
3.4a
2.3b
2.1c
È
0.53
0.53
0.53
0.53
0.30
0.30
0.30
0.30
441 ^ 14
584 ^ 11
612 ^ 25
554 ^ 16
512 ^ 17
563 ^ 21
243 ^ 10
295 ^ 13
0.282
0.653
0.915
0.983
0.62 ^ 0.02
0.90 ^ 0.03
155 ^ 6
264 ^ 10
298 ^ 20
552 ^ 19
565 ^ 32
0.72d
0.72d
0.163
0.163
0.093
0.061
168 ^ 11
a Obtained in the basic hydrolysis, Table 3. b Obtained from the intercept of the c vs. [MCH] plot Mc \ k K ] (kc K ] kc{KA)[MCH]N.
c
c
2
c
2 c
c Obtained from the intercept of the d vs. [MCH] plot (d \ k K KA ] kccK KA[MCH]). d Assumed value to determined kc and kcc from c and d
c
c
c
2
c
c
2
2
values, respectively.
fectly straight line, as predicted by eqn. (6); the bimolecular
the transition state. In the reaction of secondary amines with
alkyl nitrites, a four-center transition state33 has been postu-
lated. Even the possibility of a six-membered ring, in which
the participation of a water molecule is required, has been
considered. The strong solvation of the leaving alkoxide
undoubtedly plays a crucial role in the transition state of the
process. The removal of the alcohol is particularly favored
when the NO transfer to an amine is promoted by an alkyl
nitrite (of suitable structure) inside the cavity of an ionized
b-CD molecule. The ionized ÈO~ of a CD molecule will form
H bonds with either water molecules or with the amine also
included in the CD cavity. This special arrangement of the
reactants in the transition state, shown in Scheme 8 with a
water molecule participating in the Ðxation of the reagents to
the ionized host, should result in a strong decrease in the acti-
vation energy, even though the gain in the entropy of activa-
tion will not be negligible. Only a transition state like this,
however, accounts for the higher kcc values over those of kw.
rate constants kc (or kc{) and kcc have been determined respec-
2
2
2
tively from the slopes of the corresponding plots: c (or d) vs.
[MCH] (or [PiP]) and their values are given in Tables 5 (for
PiP) and 6 (for MCH).
Discussion
The most striking features of the results in Tables 4 to 6 are as
follows. Free 1P1P is the most reactive alkyl nitrite towards
all the amines studied here, but the reactivity of complexed
1P1P decreases with respect to that of uncomplexed substrate,
and the decrease depends upon whether the b-CD molecule is
neutral or ionized; kc for the system PyR ] 1P1P is more
2
than 20-fold lower than kw when the reaction occurs at pH
2
11.20 (neutral b-CD), but a reduction of only 3-fold is
observed in alkaline conditions (ionized b-CD). In contrast,
the reactivity of complexed 2P1P or 3P1P with PyR (kc) is the
2
2
2
Likewise, this picture for the transition state may explain the
lower reactivity of 1P1P because, due to the hydrophobicity of
the ÈCH CH moiety, 1P1P is more deeply enclosed inside
same as that of the free substrate, while the reaction between
complexed 2P1P or 3P1P with free PiP is faster than the reac-
tion between free substrates. The enhancement is quite strong
in the case of the complexed reactants with ionized b-CD, and
the e†ect of increasing reactivity is even higher for the reaction
2
3
the b-CD cavity; thus an arrangement like that of Scheme 8
would force the ethyl moiety to leave the b-CD cavity. The
proposed structure for the transition state also explains the
much lower kc values compared to kw, and the absence of step
between both complexed substrates (kcc); a 10-fold increase is
2
found in the systems 3P1P ] MCH and 2P1P ] PiP medi-
2
2
kcc when the reaction is studied in a bu†er of the amine, that
ated by b-CD.
2
is to say in conditions of non-ionized b-CD. Finally, the struc-
An increase in the rate constant of the rate determining step
means a decrease in the activation energy; therefore, this must
occur when the reaction goes through both complexed sub-
strates. As the increasing reactivity of the complexed reagents
is especially important when the complexation occurs with
ionized b-CD, a particular way of Ðxing both reagents in the
transition state of the reaction should take place with ionized
b-CD. A possible explanation could be the formation of
channel-like structures that, besides serving to Ðx the reacting
species in close proximity, might intervene in the formation of
ture of 3P1P appears the most suitable for producing a tran-
sition state like that described in Scheme 8; in fact, this alkyl
nitrite, which is the least reactive in the absence of b-CD,
shows the greatest catalytic e†ect in the presence of b-CD and
it is higher with PiP than with MCH.
Conclusions
Ionized b-CD catalyzes the basic hydrolysis of alkyl nitrites.
The present study reveals the crucial importance of the sub-
strate structure to the degree of the observed catalysis, which
is due to the formation of productive 1 : 1 inclusion complexes
between RONO and ionized b-CD. The b-CD behavior in the
catalysis of the process mimics the enzyme action, especially in
the case of 1-phenyl-1-propyl nitrite: potential inhibitors, such
as the monomer of dodecyltrimethylammonium bromide,
inÑuence the ““activityÏÏ of b-CD in a clear case of allostery.
Ionized b-CD also inÑuences the nitrosation of PyR, PiP, and
MCH by phenyl-1-propyl nitrites. The nitrosation of PyR by
3P1P and 2P1P is enhanced by the presence of b-CD, but it is
inhibited when NO transfer to PyR is promoted by 1P1P. The
Scheme 8 Postulated transition state for the nitrosation between
complexed PiP and 3P1P nitrite.
1034
New J. Chem., 2000, 24, 1025È1035

View Article Online
9
T. A. Gadosy and O. S. Tee, J. Chem. Soc., Perkin T rans. 2, 1995,
71; T. A. Gadosy and O. S. Tee, Can. J. Chem., 1996, 74, 745.
nitrosation of PiP and MCH is catalyzed by b-CD, no matter
which alkyl nitrite transfers the nitroso group. The rate con-
stant of the reaction of complexed amine with free 3P1P (or
2P1P), or of complexed RONO with free amine, or between
both complexed reactants, proved to be much higher than the
rate constant corresponding to the reaction between free sub-
strates. Finally, comparison of the data obtained in the study
of the nitrosation reaction carried out in bu†ers of its own
amine (conditions of neutral b-CD) and in alkaline media
leads us to describe important characteristics of the transition
state of the reaction, in which the solvation of the alcoholic O
atom, along with the participation of the ionized ÈO~ group
of a b-CD molecule that Ðxes the reactants in the highly
ordered transition state, are assumed. All these characteristics
are in agreement with the large negative entropies of activa-
tion found for the reaction in water and account for the higher
values of the rate constants corresponding to the processes
mediated by b-CD, as compared to the same processes
occurring in water.
10 J. Aqvist and V. Luzhkov, J. Am. Chem. Soc., 1998, 120, 6131.
11 E. Iglesias, L. Garc•aÈR•o, J. R. Leis, M. E. Pena and D. L. H.
Williams, J. Chem. Soc., Perkin T rans. 2, 1992, 1673.
12 S. Oae, N. Asai and K. Fujimore, J. Chem. Soc., Perkin T rans. 2,
1978, 571.
13 N. S. Isaacs, Physical Organic Chemistry, Longman ScientiÐc &
Technical, Essex, UK, 1987, pp. 467È484.
14 E. Iglesias and A. Fernandez, J. Chem. Soc., Perkin T rans. 2,
1998, 1691.
15 E. Iglesias, J. Am. Chem. Soc., 1998, 120, 13057.
16 C. A. Haskard, B. L. May, T. Kurucsev, S. F. Lincoln and C. J.
Easton, J. Chem. Soc., Faraday T rans., 1997, 93, 279.
17 G. GonzalezÈGaitano, A. Crespo, A. Compostizo and G. Tard-
ajos, J. Phys. Chem., 1994, 98, 6158.
18 L. A. God•nez, S. Patel, G. M. Criss and A. E. Kaifer, J. Phys.
Chem., 1995, 99, 17449; M. D. Johnson and V. C. Reinsborough,
J. Solution Chem., 1994, 23, 185.
19 S. Li and W. C. Purdy, Chem. Rev., 1992, 92, 1457.
20 W. A. Noyes, Organic Syntheses, Wiley, New York, 1943, vol. II.
21 L. Garc•aÈR•o, E. Iglesias, J. R. Leis, M. E. Pena and A. R•os, J.
Chem. Soc., Perkin T rans. 2, 1993, 29.
22 Determined in water at [HCl] \ 0.014 M following the method
of benzoylacetone solubilization: A. Dom•nguez, A. Fernandez,
N. Gonzalez, E. Iglesias and L. Montenegro, J. Chem. Educ.,
1997, 74, 1227.
Acknowledgement
Financial support from the Direccion General de
Investigacion Cient•Ðca y Tecnica of Spain (Ministry of Edu-
cation and Science), project PB96-1085, is gratefully acknow-
ledged.
23 J. Lin, F. Djeda•niÈPilard, P. Guenot and B. Perly, Supramol.
Chem., 1986, 7, 175.
24 E. Junquera, L. Pena and E. Aicart, L angmuir, 1995, 11, 4685.
25 K. J. Laidler and P. S. Bunting, T he Chemical Kinetics of Enzyme
Action, 2nd edn, Claredon Press, Oxford, UK, 1973, p. 370; P. C.
Engel, in T he Chemistry of Enzyme Action, ed. M. I. Page, Else-
vier, Amsterdam, 1984, ch. 3.
References and notes
1
2
W. Saenger, Angew. Chem., Int. Ed., Engl., 1980, 19, 344.
J. Szejtli, Chem. Rev., 1998, 98, 1743; J. Szejtli, Cyclodextrin T ech-
nology, Kluwer, Dordrecht, The Netherlands, 1988.
O. S. Tee, Carbohydr. Res., 1989, 192, 181; O. S. Tee, Adv. Phys.
Org. Chem., 1994, 29, 1.
(a) J. B. A. Ross and A. J. Orstan, J. Phys. Chem., 1987, 91, 2739;
(b) S. K. Dogra and S. J. Santra, J. Photochem. Photobiol. A:
Chem., 1996, 101, 221; (c) E. Iglesias, V. OjeaÈCao, L. Garc•aÈRio
and J. R. Leis, J. Org. Chem., 1999, 64, 3954.
(a) G. Durocher and S. Nigam, J. Photochem. Photobiol. A:
Chem., 1997, 103, 143; (b) S. Hamai, J. Phys. Chem. B, 1999, 103,
293; (c) S. Hamai, T. Ikeda, A. Nakamura, H. Ikeda, A. Ueno and
F. Toda, J. Am. Chem. Soc., 1992, 114, 6012.
(a) H.-J. Schneider, F. Hacket and V. Rudiger, Chem. Rev., 1998,
98, 1755; (b) C. T. Yim, X. X. Zhu and G. R. Brown, J. Phys.
Chem. B, 1999, 103, 597.
(a) K. Takahashi, Chem. Rev., 1998, 98, 2013; (b) O. S. Tee, M.
Bozzi, J. J. Hoeven and T. A. Gadosy, J. Am. Chem. Soc., 1993,
115, 8990; (c) M. Fukudome, Y. Okabe, D.-Q. Yuan and K.
Fujita, Chem. Commun., 1999, 1045.
26 O. S. Tee, M. Bozzi, N. Clement and T. A. Gadosy, J. Org. Chem.,
1995, 60, 3509; O. S. Tee and J. B. Giorgi, J. Chem. Soc., Perkin
T rans. 2, 1997, 1013.
3
4
27 N. Sarkar, K. Das, D. Nath and K. Bhattacharyya, Chem. Phys.
L ett., 1992, 196, 491.
28 L. A. God•nez, L. Schwartz, C. M. Criss and A. E. Kaifer, J. Phys.
Chem. B, 1997, 101, 3376.
29 M. Barra, R. H. de Rossi and E. B. de Vargas, J. Org. Chem.,
1987, 52, 5004.
5
30 (a) H. K. Hall, J. Am. Chem. Soc., 1957, 79, 5441; (b) E. Iglesias,
J. R. Leis and M. E. Pena, L angmuir, 1994, 10, 662; (c) S. P.
Ewing, D. Lockshon and W. P. Jencks, J. Am. Chem. Soc., 1980,
102, 3072.
6
7
31 F. M. Jones and E. M. Arnett, Prog. Phys. Org. Chem., 1974, 11,
263.
32 O. S. Tee, T. A. Gadosy and J. B. Giorgi, Can. J. Chem., 1996, 74,
736.
33 S. Oae, N. Asai and K. Fujimore, J. Chem. Soc., Perkin T rans. 2,
1978, 1214.
8
O. S. Tee and X. Du, J. Am. Chem. Soc., 1992, 114, 620; O. S. Tee
and J. B. Giorgi, J. Chem. Soc., Perkin T rans. 2, 1997, 1013.
New J. Chem., 2000, 24, 1025È1035
1035