Enol nitrosation revisited: determining reactivity of ambident nucleophiles

Article abstract of DOI:10.1002/ejoc.200900498

Enols are one of the most Important types of ambident nucleophiles being widely used as reagents in organic chemistry, The relevance of enols has led to considerable interest in developing methods to determine the reactivity of their nucleophilic centers, In this sense, the mainstream, literature works on this topic make use of a. combination of overall rate constants together with the analysis of the reaction products, By knowing the product ratio it is possible to determine the ratio between the reaction rates on each site, Thus, the reactivity for each, nucleophilic position can be obtained, This is a reliable approach as long as the isolation or in situ characterization of the reaction products can be carried out, In the case of unstable and/or interconvertible products where the use of identification techniques is not possible, an alternative methodology must be found, For that: reason, our research group has developed a model that allows us to study and quantify separately the reaction rates of enol nucleophilic centers even if only one final reaction product is obtained, This model is based on the fact: that nitrosation of enols shows well-differentiated behavior depending on whether the reaction proceeds through the carbon or the oxygen atom, The present study provides insights into the ambident nature of enols as well as a methodology for determining the chemical reactivity of their nucleophilic centers.

Full text of DOI:10.1002/ejoc.200900498

FULL PAPER
DOI: 10.1002/ejoc.200900498
Enol Nitrosation Revisited: Determining Reactivity of Ambident Nucleophiles
[a]
[b]
[a]
[c]
Luis García-Río,* Juan C. Mejuto, Mercedes Parajó, and Moisés Pérez-Lorenzo
Keywords: Enols / Ketones / Nitrosation / Reaction mechanisms / Tautomerism
Enols are one of the most important types of ambident nu-
cleophiles being widely used as reagents in organic chemis-
try. The relevance of enols has led to considerable interest
in developing methods to determine the reactivity of their
nucleophilic centers. In this sense, the mainstream literature
works on this topic make use of a combination of overall rate
constants together with the analysis of the reaction products.
By knowing the product ratio it is possible to determine the
ratio between the reaction rates on each site. Thus, the reac-
tivity for each nucleophilic position can be obtained. This is
a reliable approach as long as the isolation or in situ charac-
terization of the reaction products can be carried out. In the
case of unstable and/or interconvertible products where the
use of identification techniques is not possible, an alternative
methodology must be found. For that reason, our research
group has developed a model that allows us to study and
quantify separately the reaction rates of enol nucleophilic
centers even if only one final reaction product is obtained.
This model is based on the fact that nitrosation of enols
shows well-differentiated behavior depending on whether
the reaction proceeds through the carbon or the oxygen
atom. The present study provides insights into the ambident
nature of enols as well as a methodology for determining the
chemical reactivity of their nucleophilic centers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
quent attack at the second site occurs on a time scale faster
than that of the detection of the species involved in the
reaction (Scheme 1).
Enols and enolate ions form the most important type of
ambident nucleophiles. The term “ambident” is applied to
describe all chemical species whose molecular entities pos-
sess two alternative and strongly interacting distinguishable
reactive centers, to either of which a bond may be made in
a reaction. In this sense, it is traditionally accepted that in
order to determine the reactivity of each site, these reactive
centers must be connected in such a way that the reaction
at either site stops or greatly retards subsequent attack at
the second site. That would allow either the isolation or in
situ characterization of the final products and, therefore,
the discrimination between the reactivity of each position.
In other words, by knowing the product ratio it is possible
to determine the ratio between the reaction rates on each
site. However, in enol chemistry there are cases in which
this discrimination cannot be carried out by means of iden-
tification techniques. This is due to the fact that the subse-
Scheme 1.
In such cases, because a single final product is obtained,
only the overall reaction rate can be calculated, but not the
ratio between the rates on each site. For that reason, our
research group has developed a kinetic model that allows
us to study and quantify separately the reaction rates of
enol nucleophilic centers even if only one final product is
obtained. This model is based on the fact that nitrosation
of enols shows a well-differentiated behavior depending on
whether the reaction proceeds through the carbon or the
oxygen atom.
[
a] Departamento de Química Física, Facultade de Química, Uni-
versidade de Santiago de Compostela,
1
5782 Santiago de Compostela, Spain
Fax: +34-981-595-012
E-mail: luis.garcia@usc.es
[
[
b] Departamento de Química Física, Facultade de Ciencias, Uni-
versidade de Vigo,
With this aim we have investigated the nitrosation reac-
tion of barbituric acid (HB) in water. However, as prelimi-
3
2004 Ourense, Spain
c] Departamento de Química Física, Facultade de Química, Uni- nary work we re-examined nitrosation of acetylacetone
versidade de Vigo,
6310 Vigo, Spain
[1]
(
AcAc). The reason for this choice is that AcAc is a less-
3
complex reactive system and the conclusions drawn from
its kinetic analysis will help in elucidating the mechanism
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900498.
Eur. J. Org. Chem. 2009, 4525–4533
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L. García-Río, J. C. Mejuto, M. Parajó, M. Pérez-Lorenzo
FULL PAPER
of HB nitrosation and, therefore, in building up a kinetic
model to describe quantitatively the ambident nature of en-
ols. AcAc nitrosation shows a simultaneous nucleophilic
and general-base catalysis. The observed nucleophilic catal-
ysis points out to a C-nitrosation mechanism, where the
rate-limiting step consists of electrophilic attack at the ole-
finic carbon atom of the AcAc enol form. In fact, catalysis
by nucleophiles is a distinctive feature of alkene nitrosation.
In contrast, the general-base catalysis observed in the pres-
ence of buffers points to an O-nitrosation mechanism in-
volving a rate-limiting proton transfer. Such experimental
behavior is compatible with the one observed in the litera-
ture for other alcohol nitrosation reactions. This simulta-
neous catalysis constitutes the confirmation of two indepen- Figure 1. Influence of HB concentration on kobs for HB nitrosation
dent reactions on the carbon and oxygen atom of an enol in acidic media. Ionic strength 1.00  (NaClO ); T = 25.0 °C. (᭹)
4
+
+
+
+
[
1
H ] = 0.10 ; (᭺) [H ] = 0.20 ; (᭿) [H ] = 0.30 ; (ᮀ) [H ] =
(Scheme 2).
.00 .
would constitute the predominating reaction, whereas at
high acidity a mechanism through the neutral form of the
enol would prevail.
Scheme 2.
In contrast, the much higher acidity of HB compared to
AcAc
[2]
HB
[3]
AcAc (pKa
= 8.79 and pKa = 4.04 ) will give rise
to a more complex reaction scheme, as the nitrosation of
the carbanion enolate ion will constitute an additional reac-
tion pathway. This additional operating mechanism will re-
markably affect the kinetic behavior of the overall process,
which is proposed to involve both enol and carbanion enol-
ate forms of HB.
Figure 2. Influence of H+ concentration (HClO
nitrosation. Ionic strength 1.00  (NaClO ); [HB] = 1.0ϫ10 ; T
25.0 °C.
4
) on kobs for HB
–
3
4
=
Results
–
–
In the presence of nucleophiles such as Cl , Br , or
–
Under all experimental conditions used in this study, the SCN , HB nitrosation undergoes a remarkable catalytic ef-
reaction rate for HB nitrosation showed a first-order depen- fect (Figure 3). This well-reported behavior
[
4–7]
is a conse-
dence on [HNO ]. This behavior completely rules out a quence of the formation of the corresponding nitrosating
2
rate-limiting enolization, as a zero-order dependence on agents (NOCl, NOBr, and NOSCN), whose catalytic effi-
[
HNO ] should be found in such a case. In addition, the cacy lie in the value of their equilibrium constant of forma-
2
–3
–1 [8]
–2 –1 [9]
pseudo-first-order rate constant for HB nitrosation showed tion (KNOCl = 1.14ϫ10  ; KNOBr = 5.10ϫ10  ,
in all cases a linear dependence on [HB] (Figure 1). As and KNOSCN = 32 –
1[10]
).
shown in this plot, the slopes of the linear fits increase as
The observed nucleophilic catalysis can be attributed to
a reaction pathway where nitrosation takes place through
+
[
H ] rises ([HClO ] = 0.10–1.00 ).
4
Figure 2 shows the influence of acid concentration the carbanion enolate form. Given the absence of a trans-
HClO ) on k for HB nitrosation. The obtained results ferable proton in the conjugate base, the only possible rate-
(
4
obs
+
+
display two well-differentiated dependences on [H ]. Thus, limiting step will be the attack of NO either at the carbon
+
at [H ] Ͻ 0.10  a nonlinear dependence of k
on acid or the oxygen atom of the deprotonated form of HB. Like-
obs
concentration is found, whereas the rate constant exhibits a wise, this experimental behavior can be also ascribed to a
+
linear dependence at [H ] Ͼ 0.10 . This dual behavior simultaneous reaction pathway where HB nitrosation pro-
points out to the involvement of different and simultaneous ceeds through the carbon atom of the neutral enol form
operating mechanisms in the nitrosation reaction. Thus, at (Scheme 3). This claim is supported by studies on alkene
[
11]
low acidity a reaction through the carbanion enolate ion nitrosation where this catalysis is a distinctive feature.
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Enol Nitrosation Revisited
Figure 3. Influence of nucleophile concentration on kobs for HB
–
3
4
nitrosation. Ionic strength 1.00  (NaClO ); [HB] = 1.0ϫ10 ;
+
–3
–
–
–
[
H ] = 1.0ϫ10 ; T = 25.0 °C. (᭹) Cl ; (᭺) Br ; (᭿) SCN .
–
Scheme 3.
Figure 4. (a) Influence of Br concentration on kobs for HB nitro-
–3
4
sation. Ionic strength 1.00  (NaClO ); [HB] = 1.0ϫ10 ; T =
+
–3
+
–3
+
2
=
5.0 °C. (᭹) [H ] = 1.0ϫ10 ; (᭺) [H ] = 5.0ϫ10 ; (᭿) [H ]
–
2
+
–1
+
–1
5.0ϫ10 ; (ᮀ) [H ] = 4.0ϫ10 ; (᭡) [H ] = 8.0ϫ10 
+
In Scheme 3 a two-stage process through a nitroso carbo- (some data omitted for clarity). (b) Influence of H concentration
on kobs for HB nitrosation. Ionic strength 1.00  (NaClO ); [HB]
4
cation intermediate is proposed. This intermediate is ex-
–
3
–
–2
plained by a cyclic onium structure[
6,12]
= 1.0ϫ10 ; [Br ] = 5.0ϫ10 ; T = 25.0 °C.
involving either a
fully bonded three-membered ring or an electrostatic inter-
action between the nitrogen atom and the developing posi-
tive charge on carbon.
Accordingly, the presence of Cl , Br , and SCN in the formation). This is compatible with the effects observed for
reaction medium catalyzes the nitrosation of both HB carb- alcohol nitrosation in the presence of buffers,
Figure 5 shows that HB nitrosation is also a buffer-cata-
lyzed reaction (see also Figures S3 and S4, Supporting In-
–
–
–
[
13]
for which
anion enolate and enol forms. In this sense, our experiments general acid–base catalysis is a distinctive feature.
on the influence of proton concentration on the reaction
rate in the presence of nucleophiles provide evidence for the
coexistence of these reaction pathways. Thus, as shown in
Figure 4a, there is an enhancement in the catalytic effect of
–
Br as acidity is increased. Because the amount of carban-
ion enolate form is decreasing, this effect must be due to
the catalysis of the enol nitrosation pathway (see also Fig-
ures S1 and S2 in the Supporting Information).
In other words, if the carbanion enolate pathway was the
only nucleophile-catalyzed route of HB nitrosation for a re-
–
action series where there is a set amount of added Br and
+
+
a variable amount of H , a leveling off in the k vs. [H ]
obs
plot should be obtained. As seen in Figure 4b, not even at
high proton concentrations can a plateau be reached. On
the contrary, the rate constant keeps increasing with acid
concentration (as it happens in Figure 2). This observation
points to a simultaneous nucleophile-catalyzed enol path-
way.
Figure 5. Influence of dichloroacetic acid buffers on kobs for HB
nitrosation. Ionic strength 1.00  (NaClO ); [HB] = 1.0ϫ10 ; T
4
–3
=
25.0 °C. (᭹) pH = 0.77; (᭺) pH = 1.16; (᭿) pH = 1.52; (ᮀ) pH
= 2.09 (some data omitted for clarity).
Eur. J. Org. Chem. 2009, 4525–4533
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L. García-Río, J. C. Mejuto, M. Parajó, M. Pérez-Lorenzo
FULL PAPER
Nevertheless, in contrast to alcohols, HB O-nitrosation
It may be suggested that the catalytic effects observed in
can be described by an irreversible base-catalyzed process. the presence of buffers might be ascribed to a nucleophilic
This claim is supported by the results obtained from 13
catalysis instead of an O-nitrosation mechanism. Thus, the
NMR and DEPT spectral analyses, where the oxime is de- buffer base would act as a nucleophilic catalyst towards C-
C
–
–
–
tected as the only final product of the reaction between HB nitrosation, in a fashion analogous to Cl , Br , or SCN ,
+
and NO . In this sense, it is well known that the identifica- through formation of an acyl nitrite as the ultimate ni-
tion of the products of a reaction helps to define the reac- trosating agent. As a consequence, the catalysis found in
tion course, as the proposed mechanism must account for the presence of buffers would be due to an increase in the
their formation.
nitrosating agent concentration as buffer concentration is
On the basis of the identification of the final product, we increased. Although this may seem like a reasonable as-
can deduce that alkenyl nitrite formation is followed by two sumption, the results obtained in this study confirm with-
consecutive fast steps: the internal rearrangement of the O- out a doubt the nature of the O-nitrosation step, ruling out
nitroso species to give the C-nitroso compound, and the the idea of buffer-catalyzed C-nitrosation (for a comprehen-
subsequent tautomerization to the more stable oxime sive discussion see Supporting Information, Section 3).
(Scheme 4). As a result, even though alcohol nitrosation is
Additional experiments with HB derivatives have been
a reversible process, we will consider the reaction between carried out in order to elucidate entirely the mechanism of
+
the oxygen atom of the HB enol form with NO as a vir- HB nitrosation. Thus, nitrosation of 1,3-dimethylbarbituric
tually irreversible process. In addition, and regarding the acid (13HB) and 5,5-dimethylbarbituric acid (55HB) has
nature of the O-nitrosation step, it must be noted that the been studied (Scheme 5).
enol forms of β-diketones such as HB show two different
oxygen atoms as potential nucleophilic centers: the carbonyl
oxygen atom and the alcohol oxygen atom. As a result, two
different reaction pathways may be suggested (Scheme 4).
Such pathways are kinetically indistinguishable and have
been deeply discussed in previous work.[
1]
With regard to the internal rearrangement shown in
Scheme 4, it must be said that O-nitroso compounds are
well known among the potential NO group donors in nitro-
Scheme 5.
13HB nitrosation presents a similar kinetic behavior to
sation chemistry. Thus, many reactions described in the lit- the one observed for HB, that is, first-order dependence on
+
erature involve intramolecular transfer of the nitroso group. [HNO ] and [13HB], dual dependence on [H ], as well as
2
Typical examples are the O–NOǞN–NO migrations ob- both nucleophilic and general-base catalyses (see Support-
[14]
served in the nitrosation of amides and ureas, amino ac- ing Information, Section 4). The only difference found is a
ids[
15]
in acidic media, and hydroxylamines;[16] the C– lower reactivity, presumably due to the lower acidity of
NOǞN–NO migrations found in the nitrosation of in- 13HB (pKa1
3HB
= 4.68 ). In contrast, 55HB gives rise to no
[3]
[
17]
doles in acidic media; and the N–NOǞC–NO migrations reaction under any of the experimental conditions used.
observed in the Fischer–Hepp rearrangement.[ Also, S– This lack of reactivity confirms the enol formation as a req-
NOǞN–NO migrations are common when studying nitro- uisite for nitrosation to take place. Furthermore, the ab-
18]
[19]
[20]
sation of cysteine in acidic and basic or neutral media, sence of any reaction allows us to rule out an unlikely N-
thioureas and thioproline or thiomorpholine.[22]
[
21]
nitrosation mechanism at the ureic moiety of HB.
Scheme 4.
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4
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Enol Nitrosation Revisited
Scheme 6.
–
C
On the basis of the experimental results described in this tion, see Supporting Information, Section 5), where k
,
NO
–
O
section we can formulate an initial mechanistic hypothesis
for HB nitrosation. Thus, according to the influence of pro- ate forms of HB towards NO , k
k
are the reactivity constants of the carbanion and enol-
NO
+
C
and kO
are the
NO
NOH O
2
ton concentration on the rate constant (Figure 2), we can reactivity constants of the carbon and oxygen atom of the
assume that HB nitrosation proceeds through both enol HB enol form, K is the HB enolization constant (K
=
E
E
[
23]
+
HB
and carbanion enolate forms. Besides, it has also been con- 0.05 ), KNO is the NO formation constant, and Ka and
HNO
2
firmed that HB nitrosation behaves simultaneously as a nu-
K
are the acidity constants for HB and HNO , respec-
a
2
cleophile and buffer-catalyzed process. Nucleophilic cataly- tively.
sis (Figure 3) points to a mechanism where the electrophilic
attack is rate determining. The nature of this attack will
+
depend on whether the NO reacts with the enol or the
carbanion enolate forms of HB. Thus, enol nitrosation will
involve direct attack at the carbon atom (C-nitrosation),
whereas carbanion enolate nitrosation will imply either at-
tack at the carbon or the oxygen atom. Because the conju-
(
1)
gate base of HB has no transferable proton, whether the
Equation (1) predicts both linear and nonlinear depen-
reaction proceeds through the carbanion or the enolate dences of the rate constant on proton concentration. As
form, the reaction will be nucleophile catalyzed. In contrast, shown in Figure 2, the agreement between the model results
buffer catalysis (Figure 5) points towards irreversible O- and the experimental data is satisfactory. From this nonlin-
–
–
C
O
10 –1 –1
nitrosation involving a rate-limiting proton transfer. There- ear fit, a value kNO + kNO = (1.09Ϯ0.09)ϫ10  s was
fore, in light of all these experimental observations the fol- calculated. As expected, the reaction through the carbanion
lowing mechanism depicted in Scheme 6 can be proposed.
enolate form is a diffusion-controlled process. The value ob-
The above mechanism exhibits four different routes for tained for the sum of the reactivity constants through the
C
O
HB nitrosation: two reaction pathways through the enol neutral enol form was
k
+
(kNO
)
=
NO
H O
2
7
–1 –1
and two through the HB deprotonated forms. In this sense, (9.19Ϯ1.02)ϫ10  s . Similar results were found when
while carbon and oxygen reactivity of the enol tautomer 13HB nitrosation was studied. Thus, for the N,N-dimeth-
can be easily discriminated, a kinetically indistinguishable ylated derivative of HB the values kNO + kNO
–
–
C
O
=
=
mechanism will be considered for the nitrosation of the HB (2.21Ϯ0.10)ϫ101  s
0
–1 –1
and
k
C
+
(kNO)
O
NO
2
H O
8
conjugate base.
(1.30Ϯ0.11)ϫ10 were obtained.
Discussion
HB Nitrosation in the Presence of Nucleophiles
As we explained in the previous section, the nitrosation
HB Nitrosation in the Absence of Added Catalyst
From the mechanism shown in Scheme 6 the rate law mechanism of HB shows three nucleophile-catalyzed routes,
given in Equation (1) can be derived (for a complete deduc- that is, three reaction pathways where the electrophilic at-
Eur. J. Org. Chem. 2009, 4525–4533
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L. García-Río, J. C. Mejuto, M. Parajó, M. Pérez-Lorenzo
FULL PAPER
tack is rate determining. Such pathways are the nitrosation
of the enol and the carbanion enolate forms (Scheme 6).
In the presence of nucleophiles the rate law given in
Equation (2) for HB nitrosation can be obtained (for de-
–
C
tails, see Supporting Information, Section 6), where k
,
NOX
–
O
k
are the reactivity constants of the carbanion and
NOX
C
enolate forms of HB towards NOX, k
is the reactivity
NOX
constant of the carbon atom of the enol form, and KNOX is
the equilibrium constant for the formation of the nitrosat-
ing agent.
Figure 6. Verification of Equation (3). Influence of H+ concentra-
–
tion (HClO
Ionic strength 1.00  (NaClO
4
) on slope for HB nitrosation in the presence of Br .
–
3
4
); [HB] = 1.0ϫ10 ; T = 25.0 °C.
Table 1. Reactivity constants of the enol and carbanion enolate
forms of HB with NOCl, NOBr, and NOSCN.
–
–
C
O
/ –1 s–1
C
/ –1 s–1
(
2)
NOX
k
= +k
k
NOX
NOX
NOX
7
6
3
NOCl
NOBr
NOSCN
(1.09Ϯ0.15)ϫ109
(1.73Ϯ0.33)ϫ10
(1.99Ϯ0.42)ϫ10
(3.90Ϯ2.20)ϫ10
Equation (2) is a binomial expression where the first
term corresponds to the reaction in the absence of added
catalyst, and the second one to the nucleophile-catalyzed
process. On the one hand, this expression predicts that for
a reaction series where there is a set amount of added
8
(7.78Ϯ1.18)ϫ10
6
(4.78Ϯ0.61)ϫ10
HClO but a variable amount of nucleophile a linear plot
4
–
of kobs vs. [X ] will be obtained (as shown in Figure 3). On
the other hand, the slopes of such plots [Equation (3)]
would rise in a nonlinear fashion as proton concentration
is increased.
(
3)
–
Figure 7. Correlation between the nitrosation rate constants and
As shown in Figure 6, in the presence of Br the agree-
ment between the model results and the experimental data
+
the Swain nucleophilicity index: nH = 0 (for H
2
O–NO ), n
Cl–
=
2
O
2.99 (for Cl–NO), nBr
–
= 4.02 (for Br–NO) and nSCN = 4.80 (for
–
is satisfactory (see also Figures S10 and S11 for HB nitro- NCS–NO). (᭹) Nitrosation of HB carbanion enolate form; (᭺)
–
–
sation in the presence Cl and SCN , respectively).
nitrosation of HB enol form.
Hence, by fitting Equation (3) to our experimental data,
the reactivity constants of the enol and carbanion enolate (Figure 3) would lie in the magnitude of the equilibrium
forms of HB with NOCl, NOBr, and NOSCN were ob- constant KNOSCN for nitrosyl thiocyanate formation. This
[
4–7]
tained (Table 1).
effect is well documented in the literature.
The leveling
As expected, in all cases the carbanion enolate form has offs shown in Figure 7 correspond to the diffusion-con-
a much higher reactivity than the enol tautomer. In ad- trolled rate limits of HB nitrosation. As expected, the pla-
dition, taking into account the results obtained in the ab- teau value for the carbanion enolate form (1ϫ101  s )
0
–1 –1
sence of catalysts, it can be also observed that reactivity is higher than that of the corresponding enol
decreases following the order NO+ Ͼ NOCl Ͼ NOBr Ͼ (1ϫ10  s ). This is a predictable result, as the reactivity
8
–1 –1
+
NOSCN (Figure 7).
of the negatively charged HB towards NO must be greater
The behavior shown in Figure 7 is justified on the basis than that of the neutral enol.
of the polarity of the X–NO bond. An increase in X elec-
tronegativity leads to an increase in the positive charge on
the nitrogen atom, making the nitroso group a better elec-
trophilic acceptor and, therefore, increasing its reactivity.
HB Nitrosation in the Presence of Buffers
HB nitrosation is a buffer-catalyzed reaction where the
Thus, the origin of the large catalytic effect of NOSCN reaction proceeds through the oxygen atom of the enol
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Enol Nitrosation Revisited
form, the proton transfer being the rate-limiting step
As shown in Figure 8, the agreement between the model
(Schemes 4 and 6). As we explained in the previous section, results and the experimental data is satisfactory.
this behavior is compatible with the kinetic effects observed
Therefore, by fitting Equation (6) to our experimental re-
for alcohol nitrosation,[ for which general-base catalysis sults, the nitrosation reactivity constants in the presence of
13]
is a distinctive feature.
dichloro- (DCA), trichloro- (TCA), and trifluoroacetic acid
From this mechanism the rate law given in Equation (4) (TFA) buffers were obtained (Table 2).
can be derived (for a complete deduction, see Supporting
O
Table 2. Nitrosation reactivity constants of HB in the presence of
DCA, TCA, and TFA buffers.
Information, Section 8), where kNO is the nitrosation re-
B–
activity constant of the oxygen atom of the HB enol form
towards NO in the presence of buffers.
+
O
/ –1 s–1
B
Buffer
k
NO
–
DCA
TCA
TFA
(3.23Ϯ0.07)ϫ101
(9.19Ϯ0.64)ϫ10
(2.90Ϯ0.07)ϫ10
0
9
9
The data shown in Table 2 can be used to construct a
Brønsted plot in order to determine the value for the reac-
tivity constant of the oxygen atom in the absence of buffers
(Figure 9).
(
4)
Equation (4) is a binomial expression where the first
term corresponds to the reaction in the absence of added
catalyst, and the second one to the base-catalyzed process.
This equation predicts a linear dependence of the observed
rate constant on buffer concentration (Figure 4). The slopes
of the kobs vs. [Buffer] plots will be given by Equation (5).
Equation (5) can be rewritten [Equation (6)].
(
(
5)
6)
Figure 9. Brønsted plot for general-base catalysis of HB nitrosation
by carboxylic acid buffers. Ionic strength 1.00  (NaClO ); [HB] =
4
–
3
1.0ϫ10 ; T = 25.0 °C. (᭺) Extrapolated value for water.
The Brønsted correlation allows us to obtain an extrapo-
lated value of (kO
)
= (8.12Ϯ1.01)ϫ10  s , which
7
–1 –1
NO H O
2
C
is compatible with the one obtained previously: k
NO
O
7
–1 –1
+
(k
)
= (9.19Ϯ1.02)ϫ10  s . In addition, the
NO H O
2
value for the Brønsted coefficient (β = 0.81) points to an
electrophilic attack lagging behind the proton transfer in
the transition state. Nonperfect synchronization between
[
24]
different processes is well documented.
Interpretation of Results
A comparison between the reactivity constants for
[
1]
AcAc and HB nitrosation is shown in Table 3.
In the absence of added catalyst the HB and AcAc enol
forms react at similar rates by both C- and O-nitrosation
mechanisms. Given their different properties (it must be
noted that AcAc is a more basic nucleophile) this behavior
can be justified on the basis of diffusion-controlled kinetics
for both substrates. In addition, as expected for HB, the
carbanion enolate ion is more reactive towards NO than
its corresponding enol tautomer. Owing to its nature, AcAc
does not show reaction through its deprotonated form.
Figure 8. Verification of Equation (6). Influence of H+ concentra-
tion on Y for HB nitrosation in the presence of buffers. Ionic
+
); [HB] = 1.0ϫ10–3 ; T = 25.0 °C. Nitro-
strength 1.00  (NaClO
4
sation of HB carbanion enolate form; (᭹) dichloroacetic acid; (᭺)
tricholoroacetic acid; (᭿) trifluoroacetic acid.
Eur. J. Org. Chem. 2009, 4525–4533
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4531

L. García-Río, J. C. Mejuto, M. Parajó, M. Pérez-Lorenzo
FULL PAPER
Table 3. Comparison between the reactivity constants for AcAc compared. Taking into account that the proton transfer is
and HB nitrosation.
rate-determining for O-nitrosation, the higher the acidity of
the alcohol group of the enol form of the substrate, the
faster the reaction will occur.
Conclusions
A methodology for determining chemical reactivity of
ambident nucleophiles is reported. This approach is based
on the different operating mechanisms for enol nitrosation.
Thus, C-nitrosation proceeds through a rate-limiting elec-
trophilic attack at the olefinic carbon atom of the enol tau-
tomer, whereas O-nitrosation involves a process where pro-
ton transfer is rate determining. The observed nucleophilic
and general-base catalyses constitute the confirmation of
two simultaneous but independent reactions on the carbon
and oxygen atoms of the enol. This study allows us to dis-
criminate the reactivity of these strongly interacting nucleo-
philic centers. The methodology described in this work rep-
resents an alternative to the use of identification techniques
in order to determine the nucleophilicity of ambident spe-
cies.
The results obtained in the presence of nucleophiles indi-
cate that reactivity decreases following the well-established Experimental Section
+
order NO Ͼ NOCl Ͼ NOBr Ͼ NOSCN. As we explained
General: All chemicals were of the highest commercially available
in the discussion section, this behavior is due to the polarity
of the X–NO bond. Once again, the carbanion enolate ion
purity and were used as supplied. All kinetic experiments were con-
ducted in water at 25 °C and µ = 1.0  (NaClO ). All rates were
4
displays a higher reactivity towards NOX than the one measured in a UV/Vis spectrophotometer and monitored at 280 nm
found for the neutral enol. Both enol and carbanion enolate (formation of the oxime). Typical nitrosating agent concentrations
–
5
pathways exhibit chemical-control behavior.
2
were [NaNO ] = (4–5)ϫ10 . HB, 13HB, 55HB, acid, halide, and
buffer concentrations were always in large excess over the nitrosat-
ing agent, ensuring pseudo-first-order conditions. As expected for
secondary C-nitroso compounds,[ under all the experimental con-
ditions the oxime was the only reaction product observed.
As pointed out above, AcAc is a much more basic nu-
AcAc
[2]
HB
[3]
cleophile than HB (pKa
= 8.79 and pKa = 4.04 ),
6]
which seems to suggest that AcAc should be a more reactive
species. However, as shown in Table 3, HB clearly shows
a higher reactivity than AcAc towards NOX. A tentative
explanation for this marked difference can be given on the
assumption of an intramolecular proton-assisted process
for C-nitrosation (Scheme 7).
Supporting Information (see footnote on the first page of this arti-
cle): Influences of substrate, proton, nucleophile, and buffer con-
centration on kobs for HB and 13HB nitrosation; deduction of
Equations (1), (2), and (4) and verification of Equation (3) together
with a comprehensive discussion of an alternative mechanism for
HB nitrosation.
Acknowledgments
This work was supported by the Ministerio de Ciencia y Tecnología
(
Project CTQ2008–04420/BQU) and Xunta de Galiza (PGIDIT07-
PXIB209041PR, 2007/085 and IPP Program).
Scheme 7.
[
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As shown in Scheme 7, the alcohol proton would solvate
the nucleophile leaving group, promoting the opening of the
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Received: May 6, 2009
Published Online: July 27, 2009
Eur. J. Org. Chem. 2009, 4525–4533
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4533