Cyclodextrins as enzyme models in nitrosation and in acid-base- catalyzed reactions of alkyl nitrites

Article abstract of DOI:10.1021/ja9827696

The widely studied cyclodextrin-mediated reactions of esters but not those of alkyl nitrites, together with the marked differences between the chemistry of esters and alkyl nitrites, prompted us to investigate the influence of β-cyclodextrin (β-CD) on the reactions of alkyl nitrites. Due to the particular characteristics of alkyl nitrite reactions, the system β- cyclodextrin-alkyl nitrites allows us to explore cyclodextrin's behavior under several experimental conditions, contrary to the case of esters. Therefore, general acid-base-catalyzed hydrolysis and nitrosation of amines by alkyl nitrites are studied. Alkyl nitrites of a particular structure have been chosen to clearly evidence the mimicry of enzyme catalysis by β-CD. Addition of β-CD strongly inhibits the acid hydrolysis of alkyl nitrites (a very fast reaction in water), except in the case of ethoxyethyl nitrite, where no effect is detected. The retardation of the reaction is attributed to a separation of the reagents: β-CD and alkyl nitrites form host-guest 1:1 inclusion complexes, but simple cations, such as H₃O⁺ in the present case, did not prove to include into the β-CD cavity. In fact, at constant β-CD concentrations, addition of dodecyltrimethylammonium bromide monomers (DTABr), which strongly compete with alkyl nitrites for the hydrophobic β- CD cavity and, thus, expel the alkyl nitrites, catalyzes the reaction. On the contrary, in alkaline medium, when a secondary hydroxy group of β-CD is ionized, addition of β-CD to the reaction medium strongly catalyzes the basic hydrolysis of alkyl nitrites (an extremely slow reaction in water). The degree of catalysis depends on the alkyl nitrite structure, varying from a factor higher than 100 in the case of 3-phenyl-1-propyl nitrite, to 0 (no reaction is observed) in the case of 2-phenyl-2-propyl nitrite. The effective molarities calculated for the catalysis evidence a base-catalyzed mechanism for the reaction. The strong catalysis observed with 1-phenyl-1-propyl nitrite upon the addition of DTABr is indicative of an example of allosteric activation. Finally, the nitrosation of pyrrolidine, piperidine, and cyclohexylamine by ethoxyethyl nitrite is slightly catalyzed by the presence of β-cyclodextrin. The degree of the observed catalysis depends on both the amine concentration and the structure.

Full text of DOI:10.1021/ja9827696

J. Am. Chem. Soc. 1998, 120, 13057-13069
13057
Cyclodextrins as Enzyme Models in Nitrosation and in
Acid-Base-Catalyzed Reactions of Alkyl Nitrites
Emilia Iglesias
Contribution from the Departamento de Qu ´ı mica Fundamental e Industrial, Facultad de Ciencias,
UniVersidad de La Coru n˜ a, 15071-La Coru n˜ a, Spain
ReceiVed August 3, 1998
Abstract: The widely studied cyclodextrin-mediated reactions of esters but not those of alkyl nitrites, together
with the marked differences between the chemistry of esters and alkyl nitrites, prompted us to investigate the
influence of â-cyclodextrin (â-CD) on the reactions of alkyl nitrites. Due to the particular characteristics of
alkyl nitrite reactions, the system â-cyclodextrin-alkyl nitrites allows us to explore cyclodextrin’s behavior
under several experimental conditions, contrary to the case of esters. Therefore, general acid-base-catalyzed
hydrolysis and nitrosation of amines by alkyl nitrites are studied. Alkyl nitrites of a particular structure have
been chosen to clearly evidence the mimicry of enzyme catalysis by â-CD. Addition of â-CD strongly inhibits
the acid hydrolysis of alkyl nitrites (a very fast reaction in water), except in the case of ethoxyethyl nitrite,
where no effect is detected. The retardation of the reaction is attributed to a separation of the reagents: â-CD
+
and alkyl nitrites form host-guest 1:1 inclusion complexes, but simple cations, such as H3O in the present
case, did not prove to include into the â-CD cavity. In fact, at constant â-CD concentrations, addition of
dodecyltrimethylammonium bromide monomers (DTABr), which strongly compete with alkyl nitrites for the
hydrophobic â-CD cavity and, thus, expel the alkyl nitrites, catalyzes the reaction. On the contrary, in alkaline
medium, when a secondary hydroxy group of â-CD is ionized, addition of â-CD to the reaction medium
strongly catalyzes the basic hydrolysis of alkyl nitrites (an extremely slow reaction in water). The degree of
catalysis depends on the alkyl nitrite structure, varying from a factor higher than 100 in the case of 3-phenyl-
1
-propyl nitrite, to 0 (no reaction is observed) in the case of 2-phenyl-2-propyl nitrite. The effective molarities
calculated for the catalysis evidence a base-catalyzed mechanism for the reaction. The strong catalysis observed
with 1-phenyl-1-propyl nitrite upon the addition of DTABr is indicative of an example of allosteric activation.
Finally, the nitrosation of pyrrolidine, piperidine, and cyclohexylamine by ethoxyethyl nitrite is slightly catalyzed
by the presence of â-cyclodextrin. The degree of the observed catalysis depends on both the amine concentration
and the structure.
Introduction
chain length of the ester, the CD, and the position of the
substituent on the phenyl group. The mechanism typically
involves nucleophilic attack by the ionized secondary hydroxy
groups of CD, but in other cases, general base catalysis competes
with nucleophile catalysis.
The present work reports the results obtained in the kinetic
study of the acidic and basic hydrolyses of alkyl nitrites (R-
O-NdO) (the case of general acid-base-catalyzed reactions)
and of the nitrosation reaction of amines by RONO (nucleophilic
reactions) carried out in the presence of â-cyclodextrin, with
three main objectives in mind: first, to see the â-CD effects
under conditions of neutral and ionized â-CD in two typical
mechanistic reactions; second, to understand how the substrate
structure conditions the results; and third, to examine the
RONO-CD interactions. Therefore, we studied the acid hy-
drolysis of ethoxyethyl (EEN), 1-phenyl-1-propyl (1PhPN),
Enzymes promote very fast reactions by bringing the reacting
groups together under the special conditions of the enzyme-
substrate complex, but it is clear that a major part of the very
large rate enhancements observed are simply due to the way
1
the functional groups involved are brought together. Enzyme
mimics catalyze reactions by mechanisms that are demonstrably
enzyme-like. General conclusions from work on models are that
efficient catalysis involve an initial binding interaction between
the substrate and the catalyst.2 Consequently, the easiest way
to improve binding, and for that the catalytic effect, is to modify
the substrate.
,3
Cyclodextrins (CDs) have proved to be the most enduringly
popular enzyme mimics, catalyzing various reactions. The
4
cleavage of esters in basic medium, mediated by CDs, is the
system most studied.5 In some cases, such as that with meta-
substituted phenyl acetates, cleavage is strongly accelerated; on
the contrary, the reaction of para-substituted isomers is ac-
celerated only modestly. The observed effects depend on the
,6
2
-phenyl-2-propyl (2PhPN), and 3-phenyl-1-propyl (3PhPN)
nitrites in acetic acid-acetate buffer; the basic hydrolyses of
those alkyl nitrites and also of n-butyl (BuN) and n-pentyl (PeN)
nitrites in alkaline medium; and the nitrosation of pyrrolidine,
piperidine, and N-methylcyclohexylamine in alkaline conditions.
(6) Tee, O. S.; Du, X. J. Am. Chem. Soc. 1992, 114, 620. Gadosy, T.
A.; Tee, O. S. J. Chem. Soc., Perkin Trans. 2 1994, 715. Gadosy, T. A.;
Tee, O. S. Can. J. Chem. 1996, 74, 745. Tee, O. S.; Gadosy, T. A. J. Chem.
Soc., Perkin Trans. 2 1994, 2191. Gadosy, T. A.; Tee, O. S. J. Chem. Soc.,
Perkin Trans. 2 1995, 71.
(
(
(
(
(
1) D’Souza, V. T.; Bender, M. L. Acc. Chem. Res. 1997, 20, 146.
2) Tabushi, I. Acc. Chem. Res. 1982, 66.
3) Saenger, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 344.
4) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 707.
5) Tee, O. S. Carbohydr. Res. 1989, 192, 181. Tee, O. S. AdV. Phys.
Org. Chem. 1994, 29, 1.
1
0.1021/ja9827696 CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/03/1998

13058 J. Am. Chem. Soc., Vol. 120, No. 50, 1998
Iglesias
Scheme 1
quantitative yield in basic media by reaction with the anion of
â-cyclodextrin.
Experimental Section
Alkyl nitrites were synthesized by treating the corresponding alcohol
with sodium nitrite in aqueous sulfuric acid,18 purified by fractional
distillation, and stored at low temperature over 3-Å molecular sieves
to prevent their hydrolysis. â-CD was purchased from Aldrich Co. and
was used without further purification. All other reagents were supplied
by Merck and were used as received. Sodium hydroxide was standard-
ized against primary standard potassium acid phthalate. All solutions
were prepared with doubly distilled water obtained from a permanganate
solution.
Kinetic experiments were monitored by using a Kontron-Uvikon
(model 941) UV-vis double-beam spectrophotometer, provided with
a multiple-cell-carrier thermostated by circulating water. In either the
acid or basic hydrolysis, the consumption of alkyl nitrites was followed
by recording the decreasing absorbance in the 240-250-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. All the experiments were performed at 25 °C, unless
otherwise indicated.
The chemistry of esters and alkyl nitrites shows marked
differences. The acid-catalyzed hydrolysis of alkyl nitrites is
7
8
quite fast, 500-fold faster than the reaction of esters; by
9
contrast, the basic hydrolysis of esters is a very fast reaction,
whereas the basic hydrolysis of alkyl nitrites is an extremely
9
slow process; finally, the reaction of alkyl nitrites with amines
10-12
is relatively fast.
The fact that nitrogen is more electro-
negative than carbon and has a lone pair probably explains the
significant differences between the chemistry of alkyl nitrites
and that of carboxylic esters: carboxyl chemistry is dominated
by the formation of tetrahedral intermediates, whereas it is
assumed that alkyl nitrites transfer the NdO group intact. That
is, if the acid- and base-catalyzed hydrolyses of alkyl nitrites
take place through a concerted mechanism (Scheme 1), in the
case of esters the reactions proceed via an addition-elimination
pathway, either A-1 or A-2 in the acid-catalyzed hydrolysis, or
Stock solutions of the alkyl nitrites were prepared in dioxane.
Reactions were initiated with the addition of 20 µL of a solution of
alkyl nitrite in dioxane to the rest of the reaction mixture. The
percentage of dioxane in the final reaction mixture was less than 1 vol
-4
%. The concentration of alkyl nitrite used was (1-4) × 10 M. Kinetic
experiments were carried out under pseudo-first-order conditions, with
the acid (or base) concentration at least 50 times greater than of the
alkyl nitrite. In each case, the integrated method was followed, fitting
the experimental absorbance-time data to the first-order integrated
equation and obtaining satisfactory correlation coefficients (>0.999)
2
through the well-known BAC mechanism in the nucleophilic
-
13
attack by OH .
Finally, it is convenient to indicate that, apart from the mere
mechanistic interest of the present study, a biochemical impor-
tance must be indubitably attributed to the present results. On
one hand, CDs are human foods, either in the form of orally
administered pharmaceuticals or as food additives, in both cases
being present as free cyclodextrins or as their inclusion
complexes, containing a drug, flavorer, or other guest sub-
o
and residuals. In what follows, k denotes the observed pseudo-first-
order rate constant, whose value was usually reproducible to within
2%.
Results and Discussion
Acid Hydrolysis. Alkyl nitrites (RONO) hydrolyze in acid
medium to yield the corresponding alcohol and nitrous acid.
The reaction is general acid catalyzed; the protonation of the
alcoholic-O atom, being simultaneous with the breaking of the
O-N bond in a concerted mechanism, is the rate-limiting step
of the reaction. The catalytic constant for the hydrogen ion (kH
1
4
stance. On the other hand, alkyl nitrites have pharmaceutical
applications in the control of blood pressure due to their well-
known properties as vasodilators. Alkyl nitrites cause muscle
relaxation by releasing NO, through their reaction with thiols
to afford unstable nitrosothiols that release the vasodilatory
-
1
-1
NO.15-17
≈ 500-1000 M s ) catalysis is much more important than
Alkyl nitrites typically lose their NO group by
the catalytic constant for the undissociated form of a weak acid
transferring it to amines, carbanions, thiols, etc., and as we
describe in this work, alkyl nitrites may generate NO in
7
-1 -1
(
HA), e.g., acetic acid, kHA < 0.20 M s .
The acid hydrolyses of EEN, 1PhPN, 2PhPN, and 3PhPN
were studied in aqueous acetic acid-acetate buffer of pH 4.89
in the absence and presence of â-cyclodextrin. Figure 1 shows
typical results of the variation of ko as a function of total buffer
concentration for the cases of 2PhP and 3PhP nitrites. As
expected, the rate constant increases moderately with [buffer],
describing a straight line, in accordance with eq 1, where Ka
represents the acidity constant of acetic acid (pKa 4.76).19 The
(
7) Iglesias, E.; Garc ´ı a-Rio, L.; Leis, J. R.; Pe n˜ a, M. E.; Williams, D. L.
H. J. Chem. Soc., Perkin Trans. 2 1992, 1673.
8) Lorry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
(
Chemistry, 3rd ed.; Harper & Row: New York, 1987. Isaacs, N. S. Physical
Organic Chemistry; Longman Scientific & Technical: Essex, England,
1
987; pp 462-477.
9) Oae, S.; Asai, N.; Fujimore, K. J. Chem. Soc., Perkin Trans. 2 1978,
71.
(
5
(10) Oae, S.; Asai, N.; Fujimore, K. J. Chem. Soc., Perkin Trans. 2 1978,
1
214. Challis, B. C.; Shuker, D. E. G. J. Chem. Soc., Chem. Commun. 1979,
kHA[H+]
3
15.
+
(11) (a) Casado, J.; Castro, A.; Lorenzo, F. M.; Meijide, F. Monatsh.
k ) k [H ] +
[buffer]
(1)
o
H
+
Chem. 1986, 117, 335. (b) Casado, J.; Castro, A.; L o´ pez-Quintela, M. A.;
Lorenzo-Barral, F. M. Bull. Soc. Chim. Fr. 1987, 403. (c) Calle, E.; Casado,
J.; Cinos, J. L.; Garc ´ı a-Mateos, F. J.; Tostado, M. J. Chem. Soc., Perkin
Trans. 2 1992, 987.
12) Garc ´ı a-Rio, L.; Iglesias, E.; Leis, J. R.; Pe n˜ a, M. E.; Rios, A. J.
Chem. Soc., Perkin Trans. 2 1993, 29.
13) Stewart, R. The Proton: Applications to Organic Chemistry;
Academic Press: London, 1985; Chapter 7.
14) Szejtli, J. Cyclodextrin Technology; Kluwer: Dordrecht, The
Netherlands, 1988.
K + [H ]
a
experimental data also show a strong inhibition of the reaction
by the presence of â-CD. Least-squares fitting of the data to eq
gave the results reported in Table 1; we can note that the
degree of catalysis depends on the structure of RONO.
Subsequently, we studied the influence of [â-CD] at a
constant buffer concentration (0.02-0.04 M), i.e., in conditions
(
1
(
(
(
(
15) Butler, A. R.; Williams, D. L. H. Chem. Soc. ReV. 1993, 22, 233.
16) Kobzik, L.; Reid, M. B.; Bredt, D. S.; Stamler, J. S. Nature 1994,
(18) Noyes, W. A. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II.
(19) Perrin, D. D.; Dempsey, B.; Serjeant, E. P. pKa Predictions for
Organic Acids and Bases; Chaman and Hall: London, 1981.
3
72, 546. Snyder, S. H. Nature 1994, 372, 504.
17) Lewis, R. S.; Tannenbaum, S. R.; Deen, W. M. J. Am. Chem. Soc.
995, 117, 3933.
(
1

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13059
Figure 1. Influence of the concentration of acetic acid-acetate buffer
of pH 4.89 in the acid hydrolysis of (a) 3-phenyl-1-propyl nitrite (b)
in the absence of â-CD and (2) in the presence of 4.4 mM of â-CD,
and of (b) 2-phenyl-2-propyl nitrite (b) in the absence of â-CD and
Figure 2. Influence of [â-CD] in the acid hydrolysis (acetic acid-
acetate buffer of pH 4.89) of (a) 2-phenyl-2-propyl nitrite (b); 3-phenyl-
1
-propyl nitrite at 31 °C (2); ethoxyethyl nitrite (f), and 1-phenyl-1-
(2) in the presence of 5.5 mM of â-CD.
propyl nitrite at (1) [buffer]
solid lines fit to eq 2. (b) Reciprocal plot of k (1/k ) against [â-CD];
t
) 20 mM and ([) [buffer]
t
) 40 mM;
Table 1. Intercept and Slope Values of the Linear Plots of k
o
vs
o o
[
buffer] Obtained in the Acid Hydrolysis of 3-Phenyl-1-propyl and
t
solid lines fit the linear regression.
2
-Phenyl-2-propyl Nitrites Performed at pH 4.89 (Acetic
Acid-Acetate Buffer) in the Absence and Presence of
â-Cyclodextrin at 25 °C
Scheme 2
a
c
N
N[â-CD]. Value of (kHA
H
b
Value of (k
H
+ k
H
K
c
[â-CD])/(1 + K
c
+
c
N
N
c
N
[â-CD]. d Value
k
HA
K
c
[â-CD])/(1 + K
c
[â-CD]. Value of k
/(1 + K
c
N
of kHA/(1 + K [â-CD].
c
The kinetic results obtained in the presence of CDs are often
interpreted on the basis of the similarity between the special
CD behavior and enzyme catalysis. Assuming the formation of
a 1:1 inclusion complex between CD and RONO, from Scheme
2, put forward for the case of 3PhP nitrite, one easily arrives at
eq 2, which relates the variation of ko with the host concentration
([â-CD]).
where the major part of the hydrolysis reaction proceeds via
specific catalysis (or H ion). In the case of 3PhPN, the kinetic
+
study was performed at six temperatures ranging between 10
and 37 °C. Representative results are displayed in Figure 2. As
can be seen, the increase in [â-CD] has nearly no effect on the
reaction of EEN, whereas the observed rate constant for the
cases of 1PhP and 2PhP nitrites strongly decreases as [â-CD]
increases, dropping to saturation kinetics, and the reciprocal plot
of ko (see Figure 2b) varies proportionally with [â-CD]; finally,
the observed rate constant for the hydrolysis of 3PhPN also
decreases with [â-CD] increase, but 1/ko values do not vary
linearly with â-CD concentration.
k )
o
+
c
+
c
N
(
k [H ] + k [HA]) + (k [H ] + k [HA]) K [â-CD]
H HA H HA c
N
1
+ K [â-CD]
c
(2)

13060 J. Am. Chem. Soc., Vol. 120, No. 50, 1998 Iglesias
Table 2. Experimental Conditions, Rate Constants (k ) of the Complex RONO‚CD, Obtained in the
o
w, k c), and Stability Constants (K N
o
s
Kinetic Study of the Influence of â-Cyclodextrin Concentration in the Acid Hydrolysis of Alkyl Nitrites in Acetic Acid-Acetate Buffer of pH
.89 (Experimental Kinetic Results Were Fitted to Eq 2)
4
RONO
EEN
t/°C
[buffer]/M
effect
103k w
12.5
8.21
8.53
18.5
1.96
2.80
4.91
7.58
14.2
23.4
o
/s-1
103k c
o
/s
K
c
N/M-1
25
25
25
25
0.020
0.020
0.040
0.030
0.040
0.040
0.040
0.040
0.040
0.040
no change
inhibition
inhibition
inhibition
inhibition
inhibition
inhibition
inhibition
inhibition
inhibition
3
a
a
a
1PhPN
1PhPN
2PhPN
3PhPN
3PhPN
3PhPN
3PhPN
3PhPN
3PhPN
ncr
ncr
ncr
543 ( 13
556
606
562
643 ( 21
589 ( 11
401 ( 20
358 ( 74
343 ( 17
10.4
15.0
20.0
25.0
31.0
37.1
w
0.135 ( 0.03
0.36 ( 0.03
0.59 ( 0.08
1.15 ( 0.09
2.75 ( 0.20
5.25 ( 0.18
354.5 ( 14
407 ( 19
400 ( 13
3
-1
ln k
o
) A - B(1/T), B ) -(8.1 ( 0.2) × 10 K-1; ln k c
o
) A - B(1/T), B ) -(11.9 ( 0.2) ×10 K
a
From the linear regression analysis of 1/k vs [â-CD]. EEN, ethoxyethyl nitrite; 1PhPN, 1-phenyl-1-propylnitrite; 2PhPN, 2-phenyl-2-propyl
o
nitrite; 3PhPN, 3-phenyl-1-propyl nitrite. ncr means “no complex reaction”.
2
3
The shape of ko vs [â-CD] profiles depends on the structure
of the alkyl nitrite and can be explained by considering the
formation of a nonreactive or reactive complex, which is a
consequence of the possible conformation adopted by the host-
guest complex. Nonlinear regression analysis of the experimental
data ko - [â-CD] to eq 2 yielded the results collected in Table
observed, and only for large organic dyes, long-chain surfac-
2
4
25
tants, and metal ions with organic ligands. In contrast, the
binding of simple cations appears to be relatively unfavorable;
for example, piperidinium ion binds only weakly and much less
than neutral piperidine. Therefore, we might conclude that the
main effect of the presence of â-CD in the acid hydrolysis of
alkyl nitrites is a separation of the reagents.
26
2. The following observations can be drawn: either EEN does
not form an inclusion complex with â-CD, or the reaction rate
of the complex is the same as that with the uncomplexed EEN,
since no effect of â-CD is observed; the branched alkyl nitrites,
Further arguments corroborating this point can be acquired
from the analysis of the results obtained in the study of the
influence of dodecyltrimethylammonium bromide (DTABr).
Figure 3 shows the variation of ko as a function of [DTABr]
for the representative cases of 3PhP and 1PhP nitrites studied
at acetic acid-acetate buffer concentration of 0.040 M and pH
2
PhP and 1PhP, form a nonreactive complex with â-CD, and
the complex shows the same stability in both cases; and finally,
PhPN forms a reactive 1:1 complex with â-CD, but the
3
complex is less stable than the previous alkyl nitrites (compare
4
.89 and in the presence of a fixed amount of â-CD.
N
values of Kc ).
Addition of DTABr to the reaction medium at concentrations
The noninfluence of â-CD on the acid hydrolysis of EEN
might be understood on the basis of a possible interaction of
EEN with â-CD, forming hydrogen-bonds between the ether-O
atom of EEN and the secondary hydroxy groups of â-CD. This
geometry of the complex will leave the -ONO group quite
o
-3
below the critical micelle concentration (cmc ) 1.2 × 10
M determined in water at [HCl] ) 0.014 M by following the
method of benzoylacetone solubilization ) causes an increase
27
of the reaction rate constant. The ko vs [DTABr] profile
describes a sigmoidal curve, typical of an effect modifying an
equilibrium process. In this sense, in the absence of â-CD, the
+
outside the â-CD cavity; i.e. the nucleophilic center toward H
(alcoholic-O atom) is immersed in aqueous medium, and
o
addition of DTABr at concentrations below the cmc has no
therefore no changes in the reactivity are expected.
28
effect on the reaction, but in the presence of â-CD, due to the
The results obtained from the study of the influence of
temperature on the acid-catalyzed hydrolysis of 3-phenyl-1-
propyl nitrite at an acetic acid-acetate buffer concentration of
fact that the binding constant of DTABr to â-CD (Ks ) 3000
-1 29
M ) is higher than that of alkyl nitrites (see Table 2), an
efficient competition for the CD cavity between both substrates
emerges. Then, an increase in [DTABr] increases the [RONO]
in water, i.e., not forming inclusion complexes, and the reaction
rate consequently increases until reaching again the value of ko
0
.040 M and pH 4.89 indicate that the inclusion equilibrium
N
constant Kc remains practically unchanged with varying
temperature. This fact means that the position of equilibrium is
determined mainly by the entropy of the inclusion process.
Bearing in mind the structures of both 2PhP and 1PhP nitrites,
only hydrophobic interactions with the â-CD interior could arise;
thus, steric effects hinder the approach of both the hydroxy â-CD
groups and the -O-NO group of the alkyl nitrite in forming
hydrogen bonds.
(20) Rohrbach, R. P.; Rodr ´ı guez, L. J.; Eyring, E. M.; Wojcik, J. F. J.
Phys. Chem. 1977, 81, 944.
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Soc. 1993, 115, 8990.
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J. Am. Chem. Soc. 1993, 115, 475. Park, H.-R.; Mayer, B.; Wolscham, P.;
K o¨ hler, G. J. Phys. Chem. 1994, 98, 6158.
w
The Arrhenius plot corresponding to the rate constants ko
(23) Haskard, C. A.; May, B. L.; Kurucsev, T.; Lincoln, S. F.; Easton,
+
c
c
+
(
)kH[H ]) and ko ()kH [H ]), for the case of the acid
C. J. J. Chem. Soc., Faraday Trans. 1997, 93, 279.
(24) Gonz a´ lez-Gaitano, G.; Crespo, A.; Compostizo, A.; Tardajos, G. J.
Phys. Chem. 1994, 98, 6158.
hydrolysis of 3PhP nitrite, describes good straight lines in both
cases whose slopes yield activation energy values of 68.9 and
(
25) God ´ı nez, L. A.; Patel, S.; Criss, G. M.; Kaifer, A. E. J. Phys. Chem.
995, 99, 17449. Johnson, M. D.; Reinsborough, V. C. J. Solution Chem.
1994, 23, 185.
9
8.5 kJ/mol for the reaction through the uncomplexed RONO
1
and for the reaction of the complex RONO‚â-CD, respectively.
Both figures are in agreement with the characteristics of the
reaction and also point to the formation of a complex that is
less reactive. This lower reactivity, or nonreactivity, of the
complex could be attributed to the restricted access of the
(
26) Barra, M.; de Rossi, R. H.; de Vargas, E. B. J. Org. Chem. 1987,
5
2, 5004.
(27) Iglesias, E. J. Phys. Chem. 1996, 100, 12592. Dom ´ı nguez, A.;
Fern a´ ndez, A.; Gonz a´ lez, N.; Iglesias, E.; Montenegro, L. J. Chem. Educ.
1997, 74, 1227.
+
(28) Garc ´ı a-Rio, L.; Iglesias, E.; Leis, J. R.; Pe n˜ a, M. E. Langmuir 1993,
reagent H3O to the CD cavity. In fact, whereas the binding of
9
, 1263.
29) Lin, J.; Djeda ¨ı ni-Pilard, F.; Guenot, P.; Perly, B. Supramol. Chem.
1986, 7, 175.
anions of many types by CDs has been observed, and it can be
(
quite strong,2
0-22
the binding of cations has rarely been

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13061
o
At [DTABr] > cmc , a value which increases slightly in the
presence of â-CD, as one can realize from the results in Figure
3, micelles of DTABr are also formed. The presence of cationic
micelles strongly inhibits the acid hydrolysis of alkyl nitrites:
+
alkyl nitrites solubilize into micelles, but H is excluded from
the micellar interface (where the reaction takes place) due to
electrostatic repulsion, and consequently a separation of the
2
8
reagents occurs.
Basic Hydrolysis. The basic hydrolysis of alkyl nitrites is a
very slow process, contrary to what occurs with the correspond-
-
ing esters. The nucleophilic catalysis of OH in the hydrolysis
of carboxylic esters is remarkably greater than that for alkyl
nitrites; but other marked differences also appear, such as the
absence of concurrent oxygen exchange between the nitroso
-
oxygen of the alkyl nitrite and OH during the reaction, or the
importance of steric requirements in the ester hydrolysis,
whereas polar effects of substituents on the leaving alkoxide
group are greater for alkyl nitrites than for esters. These
differences are often rationalized by saying that carboxyl
chemistry is dominated by the formation of tetrahedral inter-
3
1
mediates, whereas in alkyl nitrite reactions the NdO group is
1
1,12
transferred intact.
The relatively high electronegativity of
the N-atom and the presence of a lone pair on the nitrogen
ensure that alkyl nitrites are soft electrophiles and their
32
nucleophilic reactions are orbital-controlled processes. Con-
-
sequently, as OH is the hardest nucleophile, in accordance with
33
Pearson’s principle of hard and soft acids and bases, the
-
reaction of RONO with OH is a slow process, in which polar
effects of substituents on the leaving alkoxide group accelerate
the reaction; e.g., bromoethylnitrite hydrolyzes faster than
2
8
ethylnitrite.
-
The basic hydrolysis of RONO in water is catalyzed by OH ;
-
the observed rate constant increases proportional to [OH ], i.e.,
-
34
35
ko ) kOH[OH ]. The pKa of trifluoroethanol (TFE) is 12.4,
Figure 3. (b) Influence of DTABr concentration in the acid hydrolysis
of (a) 3-phenyl-1-propyl nitrite at [â-CD] ) 5.2 mM and (b) 1-phenyl-
1
4,36
close to that of â-CD (pKa ) 12.3).
For comparative
purposes, the hydrolysis of some alkyl nitrites catalyzed by TFE,
reacting as its anion, was studied in aqueous solution of 0.20
M sodium hydroxide. We found a linear increase in ko with
1
-propyl nitrite at [â-CD] ) 3.7 mM; acetic acid-acetate buffer of
pH 4.89 and at 0.040 M. (2) Plot of the data against free â-CD
concentration, calculated according to eq 3 by assuming K ) 3000
s
-1
-
M
; solid lines fit eq 2; for parameters, see text.
TFE concentration, i.e., ko ) kOH[OH ] + kTFE[TFE]; then the
appropriate second-order rate constant kTFE was determined from
the slope of the straight lines (see Figure 4). Values of kTFE
and kOH (obtained from the intercept) are collected in Table 3,
along with the values of the derived constant k2 (vide infra) for
comparison purposes. The second-order rate constant for the
measured in the absence of cyclodextrin, i.e., when all the
complexed RONO was pushed out of the CD cavity by the
surfactant monomers.
In the same figure, a plot of ko against free CD concentration
is also displayed. To calculate [â-CD]f in line with treatments
-
reaction with TFE anion is more than 2-fold that with OH ,
previously described,2
1,30
free â-CD concentration was deter-
and the hydrolyses of EEN and 1PhPN are faster than those of
the other studied alkyl nitrites, in accordance with the accelerat-
ing effects of electron-withdrawing substituents. Electron-
withdrawing substituents, or substituents with resonance effects,
make easy the stability of the leaving group, the alkoxide,
mined at each surfactant concentration by solving eq 3. Fitting
2
1
[
â-CD] + [â-CD]
+ [surfactant] - [â-CD] -
t
t
(K
)
s
-
[â-CD]t
R-O .
)
0 (3)
-
The influence of [OH ] at constant â-CD concentration (fixed
Ks
between 3.5 and 5.2 mM) was also analyzed. Figure 5 shows
the results corresponding to EEN, 3PhP, 1PhP, and n-pentyl
nitrites. A strong catalysis of the reaction can be observed in
w
the data thus obtained to eq 2, one determines ko ) (8.78 (
-
3
-1
and KcN ) 392 ( 13 M for the case of
-1
0
3
.08) × 10
s
w
-3 -1
-phenyl,1-propyl nitrite, and ko ) (9.1 ( 0.3) × 10
s
(31) Jencks, W. P.; Gilchrist, J. Am. Chem. Soc. 1968, 90, 2622.
N
-1
and Kc ) 515 ( 22 M in the acid hydrolysis of 1-phenyl-
-propyl nitrite. These values compare quite well with the data
Satterthwait, A. C.; Jencks, W. P. J. Am. Chem. Soc. 1974, 96, 7018.
(32) Garc ´ı a-Santos, P.; Calle, E.; Gonz a´ lez-Mancebo, S.; Casado, J.
Monatsh. Chem. 1996, 127, 997.
1
in Table 2. (At the low â-CD concentration used in these
experiments, we did not consider the reaction through the
complex in the fitting process in any case; i.e., we assumed
(33) Maskill, H. The Physical Basis of Organic Chemistry; Oxford
University Press: New York, 1985; Chapter 5.
(34) (a)Fern a´ ndez, A.; Iglesias, E.; Garc ´ı a-Rio, L.; Leis, J. R. Langmuir
1995, 11, 1917. (b) Iglesias, E.; Fern a´ ndez, A. J. Chem. Soc., Perkin Trans.
c
c
+
c
that ko ) kH [H ] + kHA [HA] was negligible.)
2
1998, 1691.
(
30) Tee, O. S.; Bozzi, M.; Clement, N.; Gadosy, T. A. J. Org. Chem.
(35) Jencks, W. P. J. Am. Chem. Soc. 1979, 101, 5774.
(36) Li, S.; Purdy, W. C. Chem. ReV. 1992, 92, 1457.
1
995, 60, 3509.

13062 J. Am. Chem. Soc., Vol. 120, No. 50, 1998
Iglesias
Figure 4. Catalysis of TFE concentration in the basic hydrolysis of
Figure 5. Variation of the observed rate constant, k
o
, as a function of
(
a) ethoxyethyl nitrite and (b) 1-phenyl-1-propyl (b) and 3-phenyl-1-
-
[OH ] in the basic hydrolysis of (a) 3-phenyl-1-propyl nitrite at [â-CD]
-
propyl (2) nitrites at [OH ] ) 0.20 M.
)
5.2 mM (2), ethoxyethylnitrite at [â-CD] ) 3.8 mM (b); (b)
1
-phenyl-1-propyl nitrite at [â-CD] ) 4.5 mM (b), and n-pentylnitrite
Table 3. Bimolecular Rate Constants for the Reaction of RONO
-
at [â-CD] ) 3.5 mM (2).
with OH (kOH) and with Trifluoroethoxide Ion (kTFE) Obtained
-
from the Study of the Influence of [TFE] at [OH ] ) 0.20 M
Scheme 3
a
k
2
c c c c
) k K , see Table 4 for values of k and K .
-
meaning that 1:1 inclusion complexes between RONO and CD
are formed. The experimental behavior observed conforms very
well to reaction between RONO and OH in the medium, along
with reaction through a complex RONO‚CD. Scheme 3 can be
proposed, from which eq 4 may be obtained to relate the
variation of ko with the concentration of â-CD.
every case. With 3PhPN, the variation of ko with [OH ] displays
an ascending curve up to saturation level reached at ap-
proximately [OH ] > 0.15 M; the reaction of n-pentylnitrite
does not depend on hydroxide ion concentration (between 0.03
and 1.1 M, the range investigated), but a strong catalysis by
the presence of 3.5 mM â-CD can be detected; thus, the
-
-
-
observed rate constant at [OH ] ) 0.10 M in the absence of
-
-
5
-1
kOH[OH ] + k K [â-CD]
â-CD is 0.99 × 10
s
(see Table 3). Finally, the plot of ko
c c
ko )
(4)
-
vs [OH ] in the hydrolysis of EEN and 1PhPN becomes a
straight line at [OH ] higher than approximately 0.15 M.
1 + K [â-CD]
c
-
Subsequently, we studied the influence of â-CD concentration
The catalysis observed can be qualitatively explained if CD
participates directly in the reaction; in other words, the complex
RONO‚CD is more reactive than the reaction of RONO not
complexed. As the pKa of â-CD is 12.3, at the above
experimental conditions, a secondary hydroxy group in the wider
rim of â-CD is ionized. Then, by comparison with TFE anion,
the reaction of the complex involves the NdO transfer to an
ionized secondary hydroxy group of â-CD, resulting in the direct
formation of the nitrosocyclodextrin, but a big difference
emerges: the nucleophilic catalysis of the bimolecular process
-
at fixed [OH ] (0.10 or 0.20 M). In the case of 3PhPN, the set
-
of kinetic experiments varying the [â-CD] at [OH ] ) 0.20 M
was performed at six different temperatures (in the range 10-
3
7 °C). Representative results are shown in Figure 6; some of
the results obtained in the case of 3PhPN are shown in Figure
6
b, and it can be seen that the experimental data sets obtained
-
at 25 °C and 0.10 or 0.20 M of [OH ] do not differ. Pseudo-
first-order rate constant, obtained over a range of (0.5-10) ×
-
3
1
0
M â-CD, gave rise to saturation kinetics in every case,

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13063
Table 4. Experimental Conditions and Parameters Obtained in the Study of the Influence of â-CD Concentration on the Basic Hydrolysis of
w
-
Alkyl Nitrites by Fitting the Experimental Data to Eq 4, Where k
o
) kOH[OH ]
-
w/s-1
/s-1
K
c
/M-1
EMa
RONO
t/°C
[OH ]/M
k
o
k
c
-
-
-
-
-
-
5
4
5
5
5
5
-3
EEN
EEN
n-BuN
n-PeN
25.0
25.0
25.0
25.0
25.0
25.0
25.0
25.0
25.0
10.4
15.0
20.1
31.0
37.1
0.10
0.20
0.20
0.20
0.10
0.20
0.20
0.10
0.20
0.20
0.20
0.20
0.20
0.20
9.5 × 10
1.8 × 10
(3.8 ( 0.1) × 10
64.5 ( 2.4
65.4 ( 0.7
51.5 ( 6.7
50.5 ( 8.0
279 ( 13
253 ( 20
-3
(4.52 ( 0.04) × 10
1.42
8.7
8.2
-3
∼2.0 × 10
∼1.5 × 10
3.8 × 10
(2.0 ( 0.2) × 10
-3
(2.1 ( 0.2) × 10
-4
1PhPN
1PhPN
2PhPN
3PhPN
3PhPN
3PhPN
3PhPN
3PhPN
3PhPN
3PhPN
(5.6 ( 0.1) × 10
-4
0.88/2.45b
7.5 × 10
(7.1 ( 0.2) × 10
reaction too slow; not good first-order reactions
-
5
5
-3 c
2.0 × 10
3.5 × 10
∼0
(2.34 ( 0.02) × 10
(2.53 ( 0.07) × 10
(0.76 ( 0.02) × 10
(1.13 ( 0.03) × 10
(1.79 ( 0.05) × 10
360 ( 10
301 ( 19
336 ( 22
324 ( 23
278 ( 18
287 ( 21
281 ( 10
-
-3 c
4.8
-
-
3 c
3 c
∼0
-
-
-
5
5
4
-3 c
-3 c
∼0.5 × 10
5.2 × 10
1.0 × 10
(4.5 ( 0.1) × 10
-3 c
(7.34 ( 0.09) × 10
a
/kTFE). b By taking the maximum value of k
on the analysis of the influence of [DTABr]. c ln k
Effective molarity ()k
(7.53 ( 0.18) × 10 K , A ) 19.4 ( 0.6.
c
c
c
) A - B(1/T), B )
3
-1
-
work. When all â-CD molecules are ionized (which occurs at
-
-
approximately [OH ] > 0.15 M), the excess of OH catalyzes
the reaction via step 1 (see Scheme 3). In those alkyl nitrites
-
where V1 ) kOH[OH ] is much slower than V2 ) kc (the cases
-
of 3PhPN and n-PeN), the excess of OH does not influence
-
the reaction; by contrast, when V1 ∼ V2, the excess of [OH ]
increases the ko values proportionally to the degree of kOH (the
cases of EEN and 1PhPN), see Figure 5.
-
In the same way, the experiments carried out at [OH ] )
0
.20 M displayed in Figure 6 correspond to conditions where
all â-CD molecules are ionized, and then an increase in [â-CD]
also increases the concentration of productive complexes. Solid
lines fit to eq 4, and the experimental conditions, along with
the values determined for the constants kc and Kc, are reported
in Table 4. A detailed inspection of the results suggests the
following.
Values of k2, the second-order rate constant for the reaction
-
1
of RONO + CD f products, determined as k2 ) kcKc in M
-
1
s , are reported in Table 3. This derived constant measures
the reactivity of CD toward the alkyl nitrite and indicates the
ability of CD to select between different RONO under nonsat-
urating conditions. As we can see, the value of k2 corresponding
to 3PhPN is the highest, also observing the highest degree of
catalysis. On the other hand, k2 values for the different alkyl
nitrites exhibit a range of catalytic ability of CD anion, showing
in all cases to be a better catalyst than TFE anion. This fact
rules out the possible action of â-CD anion as simple general
base catalyst; on the contrary, a significant inclusion of the alkyl
nitrite in the CD cavity in the transition state must take place.
In comparison with the results in Table 2, the stability
constants of RONO formed with neutral â-CD are shown to be
-
higher than those formed with ionized â-CD . In some cases,
Figure 6. Catalysis of â-CD in the basic hydrolysis of (a) ethoxyethyl
such as that with 1PhPN, the difference is very important: KsN
≈ 2Kc. In total contrast, EEN forms inclusion complexes with
ionized â-CD, but it appears to not form inclusion complexes
with neutral â-CD. Finally, in the case of 3PhPN, the stability
constants formed with either neutral or ionized â-CD no longer
-
nitrite at [OH ] ) (b) 0.10 and (2) 0.20 M, and of (b) 3-phenyl-1-
-
propylnitrite at [OH ] ) (b) 0.10 M and 25 °C, (2) 0.20 M and 25
°
C, and (1) 0.20 M and 20 °C. Solid lines fit to eq 4; for parameters,
see Table 4. In plot (b), both data sets (b,2) obtained at equal
temperature are fitted together.
N
differ from each other (compare values of Ks in Table 2 and
(or the intermolecular catalysis) in the case of TFE ion becomes
N
Kc in Table 4); in addition, as for Ks , there is no influence of
an intramolecular catalysis in the reaction of the complex
temperature on Kc.
-
4,37
RONO‚CD .
Another important fact is the difference in reactivity of both
processes, steps 1 and 2. The reaction rate of the complex, V2,
is more than 30 times faster than the rate of the bimolecular
process, V1, which in some cases cannot be detected. From the
analysis of the influence of temperature for the case of 3PhPN,
we can estimate a value of 89 kJ/mol for the activation energy
As a productive complex requires ionized â-CD, increasing
-
[
+
OH ] also increases the ionized â-CD concentration; i.e. â-CD
-
-
OH h â-CD + H2O, whose equilibrium constant is equal
-
1
to K ) Ka/Kw ≈ 40 M at the experimental conditions of this
(
37) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17, 65.

13064 J. Am. Chem. Soc., Vol. 120, No. 50, 1998
Iglesias
Chart 1
corresponding to the kOH process, i.e., for the bimolecular
reaction, whereas the Arrhenius plot corresponding to the rate
constant kc (Table 4) gives a value of 62.8 kJ/mol for the
activation energy of the hydrolysis mediated by the ionized
â-cyclodextrin. These results indicate an important stabilization
Chart 2
of the transition state of the reaction through the complexed
-
3
PhPN with respect to the reaction via OH . In this sense,
5,38
making use of the approach developed by Kurz for estimating
the stabilization of a transition state by a catalyst, we define
w
KTS ) [TS‚CD]/{[TS][CD]} ) kcKc/ko , i.e., the apparent
In line with this, 2-phenyl-2-propyl nitrite binds “perched”
-
stability constant of formation of the transition state of the CD-
mediated reaction, symbolized by TS‚CD, from the transition
state of the normal reaction (TS) and the CD. This quantity
to â-CD , and thus the NO group cannot come near the ionized
-
-O group of â-CD, as a consequence making the reaction
impossible; the same applies to 1-phenyl-1-propyl nitrite, but
to a lesser extent, as the branching effects do not completely
surround the reaction center (-NO) (perching the RONO
molecule in the CD cavity in only one side). Contrarily,
n-pentyl- and n-butyl nitrites can sit “loosely” in the â-CD
cavity, so both molecules can adjust the deepness in order to
closely approach the reacting groups; consequently, the EM is
the greatest observed. In an intermediate position is 3-phenyl-
1-propyl nitrite, which has no steric hindrance, but it sits inside
the â-CD snugly and, as the length of the molecule slightly
exceeds the deepness of the CD cavity, the reaction between
the functional groups is forced (see Chart 2).
-
1
takes values of 1642, 2395, 5200, 7000, and 21 758 M ,
corresponding to EEN, 1PhPN, n-BuN, n-PeN, and 3PhPN,
respectively. This variation of KTS with alkyl nitrite structure
is an additional proof of the transition-state binding of CD.
Along the same line, the efficiency of intramolecular
catalysis, like the complex reaction, is conveniently measured
3
7
in terms of the effectiVe molarity (EM) of the catalytic group.
The EM is the ratio of the first-order rate constant for the
intramolecular reaction, kc in our case, and the second-order
rate constant for the intermolecular reaction that proceeds by
the same mechanism under the same conditions, i.e., kTFE since
the pKa of TFE is quite similar to that of â-CD. The EM is
Potential Inhibitors (PI). To shed light on the host-guest
interaction process, we studied finally the effect of the addition
of DTABr to the reaction medium. Typical results obtained at
-
formally the concentration of the catalytic group (R-O in this
study) required to make the intermolecular reaction proceed at
the observed rate of the intramolecular process.
-
[OH ] ) 0.20 M in the presence of a constant [â-CD] (fixed
The values of EM () kc/kTFE) appear in Table 4 (entry 7).
Since these values are less than 80 M, the mechanism of â-CD-
mediated base hydrolysis of alkyl nitrites is considered a general
in the range of 2.5-3.7 mM) are plotted in Figure 7. Normally,
addition to the reaction mixture of an inert species, i.e., a
potential inhibitor here (PI), that forms a complex with CD
reduces the concentration of free CD, so that less CD‚RONO
complex is formed and ko is decreased.
3
7
base catalysis. Surprisingly, the highest EM is observed with
those alkyl nitrites forming the least stable complexes. We must
find the reason for this in the structure of RONO, which
obviously determines the way of including into the â-CD cavity,
Surprisingly, the addition of DTABr at concentrations lower
o
than the cmc causes a slight increase of ko in the hydrolysis of
-
and then the efficiency of CD catalysis. The simple systems’
3PhPN but a 3-fold increase in the case of 1PhPN. We must
also note that, contrary to the case of acid hydrolysis, ko vs
[DTABr] profiles do not describe a sigmoidal course typical of
a modification of an equilibrium step; instead, ko increases with
tighter binding to CD increases the EM, and thus makes the
desired net increase in transition-state binding possible. Mo-
lecular mechanics calculations were carried out to obtain the
dimensions and optimal geometries of guest molecules from
MOPAC calculations (PM3) for comparison purposes with the
host molecule cavity.3 The energy-minimized structures are
shown in Chart 1.
o
[DTABr]. As expected, at [DTABr] >cmc , an inhibition is
observed. This is because once micelles are formed, alkyl nitrites
also solubilize in the micellar pseudophase with the concomitant
decrease in the productive complex concentration. Although,
,39
+
contrary to the case of the reaction by H , cationic micelles
(
38) Kurz, J. L. J. Am. Chem. Soc. 1963, 85, 987.
-
increase the [OH ] at the micellar interface (also due to
(39) Ramamurthy, V. In Photochemistry in Organized & Constrained
-
Media; VCH Publishers: New York, 1991; p 319.
electrostatic effects); but, as the intermolecular catalysis by OH

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13065
Table 5. Maximum Degree of Catalysis, Measured as k
max/k w
o
o
,
max
with k
o
Being the Pseudo-First-Order Rate Constant at the
w
Maxium [â-CD] Used (∼0.01 M) and k
o
the Pseudo-First-Order
Rate Constant Observed for Each Amine at the Concentration Given
in the Absence of â-CD
[amine]
-
3
-3
-3
-3
1
.7 × 10
M
3.2 × 10
M
6.4 × 10
M
7.8 × 10
M
PyR
PIP
MCH
1.8
4.3
1.4
2.6
4.1
1.2
2.8
surrounding of the host-guest complex by the DTABr mono-
mers, displacing the hydration water molecules of the reacting
groups. (Note that the hydration shell decreases the natural
nucleophilicity of a nucleophile.) Similar catalysis by potential
inhibitors has been found in the cleavage of p-nitrophenyl
alkanoates by the addition of alcohols and alkanoate or sulfonate
3
0,40
anions.
In any event, there is no doubt that the present results
41
provide an example of allosteric activation; that is, substances
which are not substrate analogues attach to some site of the
â-CD‚RONO complex (in this case) with a resulting effect on
the catalytic reactivity.
Nitrosation of Amines. The nitrosation reaction of pyrroli-
dine (PyR), piperidine (PIP), and N-methylcyclohexylamine
(MCH) by ethoxyethyl nitrite (EEN) has also been studied in
the presence of â-CD. Reactions between alkyl nitrites and
secondary amines produce N-nitrosamines in quantitative yield.
The reaction in water is of first order with respect to the amine,
w
w
w
i.e. ko ) k2 [amine], with ko being the observed rate constant.
It has been postulated that alkyl nitrites transfer their nitroso
group to amines through a concerted mechanism with a four-
center transition state, although the possibility of a six-membered
Figure 7. Influence of [DTABr] in the basic hydrolysis of (a) 1-phenyl-
-
1
3
-propyl nitrite at [OH ] ) 0.20 M and [â-CD] ) 3.7 mM, and of (b)
10a,11c,12
ring, which includes a water molecule, was also considered.
-
-phenyl-1-propyl nitrite at [OH ] ) 0.20 M and [â-CD] ) (b) 5.2
A
The inclusion equilibrium constants (Kc ) of PyR, PIP, and
mM and (2) 2.5 mM.
3
4b
26
MCH with â-CD are reported in the literature as 6, 50, and
-
1 42
is much lower than the intramolecular catalysis by CD- (see
550 M , respectively. These host-guest inclusion constants
are for the neutral form of the amine, since the corresponding
Table 4), an inhibition of the reaction is also observed.
It should be emphasized here that the normal expected
behavior through the entire [DTABr] range was an inhibition
of the reaction. As in the previous section, due to the competition
between DTABr monomers and RONO, addition of DTABr
should expel the included RONO, with the consequent retarda-
tion of the reaction due to the lower reactivity of the noncom-
plexed RONO. The key difference, which it is important to note
here, is that, in alkaline medium, the complex between RONO
and ionized â-CD is the transition state of the hydrolysis
reaction, i.e., a true compound in which the functional groups
are covalently bound.
ammonium ions have proved to not include into the â-CD
2
6
cavity.
-
In this study, we worked with [OH ] ) 0.10 M, where all
the amine is in its unprotonated form. The nitrosation reaction
by EEN of the aforementioned amines is catalyzed by the
presence of â-CD. The degree of catalysis, measured as the ratio
max
w
max
of ko /ko (ko
being the maximum value of the observed
rate constant measured at the higher [â-CD] used (∼0.01 M),
w
and ko the observed rate constant determined in the absence
of â-CD at the same experimental conditions), first decreases
as the amine concentration increases, and second depends
strongly on the amine, giving the highest catalysis with MCH
and the lowest catalysis with PyR, see Table 5. To perform a
clear exposition of the results, we will comment on the results
of PyR separately for the other two cases.
The high catalysis degree observed with 1PhPN by DTABr
addition is better viewed as being the reaction between the
PI‚CD complex and 1PhPN; or, more exactly, due to the fact
o
that saturation kinetics is obtained at [DTABr] < cmc , this
implicates the formation of ternary complexes (PI‚CD‚RONO)
that are more reactive than the binary complex CD‚RONO.
Quantitative analysis of the results is complicated because it
contains two concentration variables, [PI] and [CD]; however,
as the most plausible cause for a qualitative reason for the
observed facts, we believe that DTABr monomers could
protrude through the narrow rim of â-CD, pushing out 1PhPN
molecules, thus acquiring a close proximity between the reacting
groups. The EM calculated using the maximum value observed
Nitrosation of Pyrrolidine. The influence of â-CD on the
nitrosation of PyR by EEN has been studied at two pH values:
(i) in pyrrolidine-pyrrolidinium chloride buffer of pH 11.15,
i.e., under conditions where the major part of â-CD molecules
-
are not ionized (pKa 12.30), and (ii) in the presence of [OH ]
(
40) Tee, O. S.; Bozzi, M.; Clement, N.; Gadosy, T. A. J. Org. Chem.
995, 60, 3509.
41) Laidler, K. J.; Bunting, P. S. The Chemical Kinetics of Enzyme
1
(
Action, 2nd ed.; Claredon Press: Oxford, U. K., 1973; p 370. Engel, P. C.
In The Chemistry of Enzyme Action; Page, M. I., Ed.; Elsevier: Amsterdam,
max
-4 -1
here (ko ) 9.98 × 10
s
at [â-CD] ) 3.69 mM; using eq
1
984; Chapter 3.
42) Tee, O. S.; Gadosy, T. A.; Giorgi, J. B. Can. J. Chem. 1996, 74,
736.
max
-3 -1
4
and data in Table 4 gives kc
) 2.0 × 10 s ) increases
(
to 2.45 M. Another possibility could be found in a particular

13066 J. Am. Chem. Soc., Vol. 120, No. 50, 1998
Iglesias
Table 6. Pseudo-First-Order Rate Constants Obtained in the Nitrosation of Pyrrolidine by Ethoxyethyl Nitrite in Pyrrolidine-Pyrrolidinium
Chloride Buffer of pH 11.15 and Total Buffer Concentration of 0.020 M as a Function of â-CD Concentration
3
1
1
0 [â-CD]/M
0.0
1.30
0.383
1.27
0.575
1.25
0.767
1.26
1.15
1.27
1.53
1.30
2.30
1.21
3.07
1.19
4.60
1.15
6.13
1.13
7.28
1.10
9.20
1.14
11.1
1.09
2
-1
0 k
o
/s
Table 7. Experimental Conditions Used in the Nitrosation of Pyrrolidine, Piperidine, and N-Methylcyclohexylamine in Basic Medium
-
e
(
[OH ] ) 0.10 M) by Ethoxyethyl Nitrite Performed in the Presence of â-CD
w/s-1
10 R/s
3
-1 a
10 R/s
3
-1 b
K
A/M-1
k
w/M-1 s-1
k
/s-1
k
2
c/M-1 s-1
[amine]/M
k
o
c
2
c
Pyrrolidine
-
-
-
3
3
3
-3
-3
-3
-3
-3
-3
1
3
6
.7 × 10
.2 × 10
.4 × 10
2.45 × 10
4.67 × 10
9.45 × 10
7.77 ( 0.08
9.51 ( 0.06
13.7 ( 0.2
γ/s-1 M-1
7.9 ( 0.1
9.7 ( 0.1
13.5 ( 0.3
6
6
6
1.45
1.46
1.48
4.52 × 10
4.52 × 10
4.52 × 10
1.93
1.59
1.29
w
-1
δ/s-1 M-2
A/M-1
Piperidine
50
w/M-1 s-1
cK
+ k c
A
/s M-2
-1
k
2
cc/M-1 s-1
[
amine]/M
k
o
/s
K
c
k
2
k
2
c
2
′K
c
-
-
-
-
3c
-3
-3
-3
-3
1
1
3
3
.7 × 10
0.57 × 10
0.57 × 10
1.05 × 10
1.05 × 10
0.332 ( 0.005
0.328 ( 0.009
0.387 ( 0.005
0.388 ( 0.004
23.5 ( 0.8
24.0 ( 1.2
25.9 ( 0.8
25.7 ( 0.6
0.34
0.34
0.32
0.32
50.9
47.3
42.4
43.9
2.0
2.1
1.3
1.28
3d
3c
3d
.7 × 10
.2 × 10
.2 × 10
50
50
50
Methylcyclohexylamine
-
-
-
-
3c
3d
3c
3d
-3
-3
-3
-3
3
3
7
7
.8 × 10
.8 × 10
.7 × 10
.7 × 10
0.67 × 10
0.67 × 10
1.25 × 10
1.25 × 10
1.22 ( 0.02
1.18 ( 0.02
2.10 ( 0.02
2.20 ( 0.02
205 ( 4
550
550
550
550
0.176
0.176
0.164
0.164
251
245
252
254
0.51
0.57
0.46
0.52
214 ( 3.5
263 ( 9
279 ( 8
a
b
[CD]) vs [â-CD]. c Experimental data fitted to eq 6 Analysis of k
d
corr
Experimental data fitted to eq 5. Least-squares fit of k
o
(1 + K
c
o
as a
e
w
function of free [â-CD]. Observed rate constants, k , measured in the absence of â-CD, and determined values for the rate constant of the
o
c
c′
cc
-3 -1 -1
nitrosation processes. To obtain k
2
, k
2
, and k
2
, we have used the values of k
c
) 3.8 × 10
s
c
and K ) 65 M , previously determined.
)
0.10 M, in which case a great part of secondary hydroxy
groups of â-CD are ionized.
Kinetic results obtained at pH 11.15 and total pyrrolidine
buffer concentration ([PyR]t) of 0.020 M as a function of [â-CD]
are collected in Table 6. As one can see, there is no change in
rate except for a very slight decrease. The average value of ko
-2 -1
is 1.13 × 10 s . At this pH value, the concentration of neutral
+
pyrrolidine is determined as [PyR] ) [PyR]tKa/(Ka + [H ]),
with Ka being the acidity constant of pyrrolidinium ion (pKa )
1
1.30).43 Then, the bimolecular rate constant for the reaction
-
1
between neutral PyR and EEN is calculated as k2 ) 1.36 M
-
1
s . This value is in perfect accordance with those reported in
Table 7 (vide infra) and with that obtained from the study in
aqueous alkaline medium of the influence of [PyR] (see Figure
8b): ko varies linearly with [PyR], with the straight line passing
through the origin and whose slope value is equal to 1.48 (
-
1
-1
0
.01 M s , i.e., the k2 value for the reaction in water.
-
Kinetic results obtained at [OH ] ) 0.10 M and [PyR] )
-
3
3
.2 × 10 M are displayed in Figure 8a. Pseudo-first-order
rate constants increase with [â-CD], giving rise to simple
saturation kinetics. Remembering that the stability constant of
the inclusion complex formed between PyR and â-CD has been
A
-1
-3
estimated as Kc ) 6 M , working at [PyR] ) 1.6 × 10 ,
-
3
-3
3
.2 × 10 , or 6.4 × 10 M, the amount of amine forming
inclusion complexes will be insignificant. On the contrary, EEN
binds to ionized â-CD, with Kc ) 65 M- being the equilibrium
1
-
constant of complex formation, and in the presence of OH ,
the basic hydrolysis reaction via both free and complexed EEN
occurs (see previous section). But, on the other hand, the reaction
rate of the nitrosation process is much higher than that of the
Figure 8. (a) (b) Influence of â-CD concentration in the nitrosation
-
4
-1 -1
basic hydrolysis; in fact, we found kOH ) 9.5 × 10
M
s ,
-
of pyrrolidine by ethoxyethyl nitrite at [OH ] ) 0.10 M and [PyR] )
whereas from the study of the nitrosation reaction in the absence
-3
3
of k
.2 × 10 M; (2) linearization of the data according to eq 5. (b) Plot
w c
o c 2
w
-1 -1
of â-CD, we found k2 ) 1.48 M s . Therefore, as a starting
and R () k + k [PyR]) against [PyR].
hypothesis, we can consider that the nitrosation of PyR could
-
The rate of disappearance of EEN is the sum of the rate of
the four reactive steps; nevertheless, in the experimental
conditions of this work, V1 , V2. In fact, plotting kow against
[PyR], the straight line goes through the origin (Figure 8b).
take place through both free EEN and the EEN‚CD complex.
On the basis of these considerations, Scheme 4 can be proposed.
(43) Andraos, J.; Kresge, A. J. J. Am. Chem. Soc. 1992, 114, 5643.

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13067
Scheme 4
Considering, then, the following mass-balance equations, [EEN]t
)
[EEN] + [EEN‚CD], [PyR]t ) [PyR], and [CD]t ) [CD],
one easily arrives at eq 5.
w
ko + RK [â-CD]
c
c
2
ko )
,
with R ) k + k [PyR] (5)
c
1
+ K [â-CD]
c
Experimental values of ko - [â-CD] were fitted to this
w
equation by means of nonlinear regression analysis, with ko
and Kc being input parameters. Table 7 contains the obtained
parameters along with the experimental conditions. Values of
R have been plotted against [PyR]; as expected, a good straight
line is described (Figure 8b) with intercept (≡kc ) (5.3 ( 0.2)
-
3
-1
c
-1 -1
×
10 s ) and slope (≡k2 )1.32 ( 0.06 M s ) statistically
significant values; in other words, the complexed EEN reacts
via transferring the -NO group both to the ionized hydroxy
group of â-CD and to pyrrolidine, and also kc compares quite
well with the value obtained in the absence of PyR (see Table
Figure 9. (a) Influence of â-CD concentration in the nitrosation
4
).
Further support for eq 5 is obtained from the linear plot of
the data in the form of ko(1 + Kc[â-CD]) against [â-CD] with
-
reaction by ethoxyethyl nitrite at [OH ] ) 0.10 M of piperidine (b,O)
-3
at [PIP] ) 1.67 × 10 M and of N-methylcyclohexylamine (2,4) at
-3
[
MCH] ) 7.7 × 10 M. Open points refer to total [â-CD], and solid
-
1
-3
Kc ) 65 M . The plot corresponding to [PyR] ) 3.2 × 10
points refer to free [â-CD]; solid lines fit to eq 6, for parameters, see
corr
A
M is also shown in Figure 8a, and, as expected, a good straight
line was described; this was also the case with the other PyR
Table 7. (b) Plots of k {) k
o
(1 + K
c
[â-CD])(1 + K [â-CD])} (b,2)
c
and of k (4,O) against free [â-CD] obtained in the nitrosation by
o
w
c
ethoxyethylnitrite, of piperidine (triangles) at [PIP] ) 3.3 × 10-3
M
concentrations (plots not shown). Values of k2 , kc, and k2 are
-
1
A
-1
collected in Table 7. The comparison of k2w and k2c values
(K
(
M
c
) 65 M and K
c
) 50 M ), and of N-methylcyclohexylamine
3 A
-
-1
circles) at [MCH] ) 3.8 × 10 M (K
c
) 65 M and K
c
) 550
indicates that both free and complexed EEN reacts practically
at the same rate with PyR. This means that the observed catalysis
is due only to the comparable rates of steps 3 and 4; but,
increasing [PyR], the rate of step 3 is being increased, while
that of step 4 remains unchanged. Consequently, the degree of
catalysis is reduced on increasing [PyR].
-
1
corr
w
2
). Solid lines fit to k ) k
o
+ γ[â-CD] + δ[â-CD] , according
to eq 6; for parameters, see Table 7.
Scheme 5
Nitrosation of Piperidine and Methylcyclohexylamine.
Typical results obtained in the nitrosation of PIP and MCH by
-
EEN at [OH ] ) 0.10 M in the presence of â-CD are shown in
Figure 9a. These amines are less reactive than PyR and more
hydrophobic, in the sense that the stability constants of the
corresponding inclusion complexes with â-CD are much higher
than those of PyR. Therefore, with PIP and MCH, the amount
of complexed amine is not negligible. Thus, we suggest that
our kinetic scheme of reaction may be represented as in Scheme
5
, put forward for the case of MCH, where, besides the basic
-
hydrolysis reaction via either OH (step 1) or ionized â-CD
(step 2), the possibility of nitrosation reactions of free EEN with
free amine (step 3), the complexed amine (MCH‚CD) with the
free EEN (step 4), or its kinetically equivalent reaction of the
free amine with the complexed EEN (step 6), and the complexed
EEN and complexed amine (step 5), are represented. The rate
of the reaction is the sum of the six reaction steps, but as with
PyR, the rate of step 1 may be ignored. Then, taking into account
that the concentrations of the species are given by [EEN]t )
[CD]t ) [CD] + [MCH‚CD], from the expressions of Kc and
A
Kc given in Scheme 5, one arrives easily to eq 6, where γ )
c
c
A
A
{kcKc + (k2 Kc + k2 ′Kc )[MCH]} and δ ) {kcKcKc
+
cc
A
k2 KcKc [MCH]} (or [PIP]) and [â-CD] represents free cyclo-
dextrin concentration, which has been determined by solving
2
A
[EEN] + [EEN‚CD], [MCH]t ) [MCH] + [MCH‚CD], and
the equation [CD] + [CD]{[amine]t - [CD]t + 1/Kc } - [CD]t/

13068 J. Am. Chem. Soc., Vol. 120, No. 50, 1998
Iglesias
Chart 3
KcA ) 0, with Kc ) 550 M-1 for the case of MCH, and KcA
A
-
1
)
50 M for the association of PIP to CD.
w
2
Figure 10. Brønsted plot of the reactivities of EEN toward oxygen
anions, â-CD anion, carbanion of malonitrile (MN), and amines.
ko + γ[â-CD] + δ[â-CD]
ko )
(6)
A
(
1 + K [â-CD])(1 + K [â-CD])
c
c
malononitrile anion (MN-),45 with EEN (log ki) are plotted
against their pKa in Figure 10. Bimolecular reactions of EEN
w
Since ko and the equilibrium constants are known, we could
calculate γ and δ values by nonlinear regression analysis of
the experimental data ko - [â-CD] fitted either to eq 6 or to its
modification in the form of ko
Kc [â-CD]) vs [â-CD]. Solid lines in Figure 9a and b correspond
to the fit of the experimental data in the two alternatives,
respectively. Values of γ and δ determined from both procedures
are collected in Table 7, along with the experimental conditions
and the input parameters used in the fitting process.
-
-
-
-
with oxygen nucleophiles OH , TFE , ClO , and CD display
a good Brønsted plot with a slope R ) -0.12 ( 0.03;
meanwhile, the reactivities with amines or the carbanion of MN
do not show any clear trend. In accordance with the values of
EM, the mechanism of the reaction of EEN with oxygen
nucleophiles is a general base-catalyzed reaction, while amines
corr
) ko(1 + Kc[â-CD])(1 +
A
-
and MN behave as intrinsic nucleophiles; then, their reactivities
with alkyl nitrites are better correlated with Ritchie’s N+
Values of γ, together with kc and Kc values reported in Table
46
12
parameter, as our group has demostrated previously. It seems
that N+ measures some property of the nucleophiles that strongly
influences reactivity of reactions and, in particular, those of NO-
transfer. Since N+ is determined kinetically, it seems that it must
contain information on transformations that take place in the
nucleophile during the course of the chemical reaction.
c
c
A
7
, afford the sum k2 Kc + k2 ′Kc . In the case of piperidine,
A
values of Kc and Kc are similar, and they are also similar to
the observed value of the aforementioned sum. If we assume
that k2 ) k2 ′ ) γ/(Kc + Kc ), a value of 0.40 M
c
c
A
-1 -1
s
can be
obtained for these rate constants. Obviously, other combinations
are also possible, but there is no reason for a big difference in
the values of the rate constants for the reaction between the
complex EEN‚CD (or PIP‚CD) and free PIP (or free EEN). In
Conclusions
-
1
-1
the same manner, a value of 0.41 M
s
can be obtained for
Acid hydrolysis of 1PhP, 2PhP, and 3PhP nitrites is inhibited
c
c
k2 ) k2 ′ in the case of N-methylcyclohexylamine; or since
by the presence of â-CD. These RONO form 1:1 inclusion
A
+
with this amine Kc . Kc, considering the sum must be equated
complexes with â-CD, but H3O , a simple cation, does not bind
c
A
c
c
c
to k2 ′Kc unless k2 . k2 ′, then we could estimate k2 ′ ) 0.46
to CD. The energy of activation of CD-mediated acid hydrolysis
is much higher than that of the reaction between free substrates.
The acid hydrolysis of EEN is not influenced by the presence
of â-CD, which has been attributed to the special way EEN
interacts with neutral CD.
-1
-1
M
s . That is, both possibilities could work.
On the other hand, from δ values, one determines k2 , that
cc
is the rate constant for the reaction between the complexes
EEN‚CD and amine‚CD. As we can see, this rate constant is
more than 3-fold the rate constant between free substrates. In
other words, there is an important decrease in free energy when
the complexed substrates react together. This may be due to
the possibility of formation of channel-like structures which,
besides serving to fix the reacting species in close proximity,
might intervene in the formation of the transition state, possibly
in the way shown in Chart 3.
In fact, the nitrosation of amines by alkyl nitrites goes through
highly ordered transition states, based chiefly on the solvent
isotope effects observed that are greater than unity that evidence
a rate-controlling step involving a proton transfer, and on the
large negative entropies of activation determined for these
On the contrary, the basic hydrolysis of ethoxyethyl, n-butyl,
n-pentyl, 1-phenyl-1-propyl, and 3-phenyl-1-propyl nitrites is
strongly catalyzed by the presence of ionized â-CD. The
catalysis is due to the formation of productive 1:1 inclusion
complexes between RONO and ionized â-CD; that is, the
complex is the transition state of the reaction in which the
reactive groups, -NO and the ionized hydroxy group of CD,
are brought together. The stability constant of the transition state
for the CD-mediated reaction depends on the structure of
RONO, being higher for the alkyl nitrites with linear hydro-
carbon chains. This characteristic explains the nonobserved
catalysis in the case of 2PhPN, in which steric hindrance of
methyl groups at both sides of the NO-group prevent reactant
groups from approaching each other. Addition of potential
inhibitors, such as DTABr, catalyzes the reaction, contrary to
what is expected. The effect is quite strong in the case of 1PhPN
1
1a,b
reactions.
Similar effects of CDs have been found in the
nuclophilic aromatic substitution reactions of 1-chloro-2,4-
dinitrobenzene and 1-fluoro-2,4-dinitrobenzene with amines.
Mechanism Characteristics. The measured reactivities of
the substrates studied here, as well as that with ClO ion and
2
6
-
44
(45) Iglesias, E. J. Chem. Res. (S) 1995, 98.
(
44) Leis, J. R.; Pe n˜ a, M. E.; Rios, A. M. J. Chem. Soc., Perkin Trans.
(46) Ritchie, C. D. Can. J. Chem. 1986, 64, 2239. Ritchie, C. D. Acc.
Chem. Res. 1972, 5, 348.
2
1995, 587.

Influence of â-CD on Reactions of Alkyl Nitrites
J. Am. Chem. Soc., Vol. 120, No. 50, 1998 13069
and can be viewed as an example of allosteric activation; that
is, DTABr monomers induce conformational changes in the
transition state.
between amine (or EEN) complex and free EEN (or amine),
with the reaction rate through both complexes being nearly
3-fold that of free EEN and MCH.
Nitrosation of amines by ethoxyethyl nitrite in alkaline
medium is enhanced by the presence of â-CD. PyR does not
form inclusion complex with â-CD, and free and complexed
EEN react with PyR at practically the same reaction rates. PIP
and MCH form inclusion complexes with â-CD. The nitrosation
can occur via either free substrates or complexed substrates, or
Acknowledgment. Financial support from the Direcci o´ n
General de Investigaci o´ n Cient ´ı fica y T e´ cnica of Spain (Proyect
PB96-1085) and from the Xunta de Galicia (Project XUGA
1
0302A95) is gratefully acknowledged.
JA9827696