Inorganic anionic oxygen-containing α-nucleophiles - Effective acyl group acceptors: Hydroxylamine ranks first among the α-nucleophile series

Article abstract of DOI:10.1023/A:1021699628721

Comparative analysis of the nucleophilicity of inorganic oxygen-containing α-nucleophiles (hydroxylamine and ClO^-, BrO^--, HOO^--, NH₂O^-, and F^- ions) covering the pK_a range from -2 to 13.81 toward 4-nitrophenyl esters (4-nitrophenyl acetate, 4-nitrophenyl p-toluenesulfonate, diethyl 4-nitrophenyl phosphate, ethyl 4-nitrophenyl ethylphosphonate, and 4-nitrophenyl dimethylcarbamate) in water at 25°C (ionic strength μ 1.0, KCl) was performed in terms of the extrathermodynamic Brosted relation. It was found for the first time that hydroxylamine anion ranks first among the series of α-nucleophiles. It is more reactive than HOO^- ion with respect to 4-nitrophenyl acetate (by a factor of ～8), 4-nitrophenyl p-toluenesulfonate (by a factor of ～4) and 4-nitrophenyl dimethylcarbamate (by a factor of ～10). The nucleophilicities of HOO^- and NH ₂O^- ions toward diethyl 4-nitrophenyl phosphate and ethyl 4-nitrophenyl ethylphosphonate are comparable. Taking into account that neutral hydroxylamine exhibits an anomalously high reactivity, as compared to not only common organic but also inorganic α-nucleophiles, it may be regarded as a unique α-nucleophile. Both neutral hydroxylamine and its anion as O-nucleophiles ensure high rates of acyl group transfer throughout a wide range of pH.

Full text of DOI:10.1023/A:1021699628721

Russian Journal of Organic Chemistry, Vol. 38, No. 9, 2002, pp. 1286 1298. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 9, 2002,
pp. 1341 1353.
Original Russian Text Copyright
2002 by Simanenko, Popov, Prokop’eva, Karpichev, Savelova, Suprun, Bunton.
Inorganic Anionic Oxygen-Containing -Nucleophiles
Effective Acyl Group Acceptors: Hydroxylamine Ranks First
among the -Nucleophile Series
Yu. S. Simanenko1, A. F. Popov1, T. M. Prokop’eva1, E. A. Karpichev1,
V. A. Savelova1, I. P. Suprun1, and C. A. Bunton2
1
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Luxemburg 70, Donetsk, 83114 Ukraine
e-mail: simanenko@infou.donetsk.ua
2
Department of Chemistry and Biochemistry, University of California,
Santa Barbara, USA
Received July 3, 2001
Abstract Comparative analysis of the nucleophilicity of inorganic oxygen-containing -nucleophiles
(hydroxylamine and ClO , BrO -, HOO -, NH2O , and F ions) covering the pKa range from 2 to 13.81
toward 4-nitrophenyl esters (4-nitrophenyl acetate, 4-nitrophenyl p-toluenesulfonate, diethyl 4-nitrophenyl
phosphate, ethyl 4-nitrophenyl ethylphosphonate, and 4-nitrophenyl dimethylcarbamate) in water at 25 C
(ionic strength 1.0, KCl) was performed in terms of the extrathermodynamic Bronsted relation. It was found
/
for the first time that hydroxylamine anion ranks first among the series of -nucleophiles. It is more reactive
than HOO ion with respect to 4-nitrophenyl acetate (by a factor of 8), 4-nitrophenyl p-toluenesulfonate
(by a factor of 4) and 4-nitrophenyl dimethylcarbamate (by a factor of 10). The nucleophilicities of HOO
and NH2O ions toward diethyl 4-nitrophenyl phosphate and ethyl 4-nitrophenyl ethylphosphonate are
comparable. Taking into account that neutral hydroxylamine exhibits an anomalously high reactivity, as
compared to not only common organic but also inorganic -nucleophiles, it may be regarded as a unique
-nucleophile. Both neutral hydroxylamine and its anion as O-nucleophiles ensure high rates of acyl group
transfer throughout a wide range of pH.
Extensive kinetic studies of the behavior of various
nucleophiles toward unsaturated electron-deficient
systems, such as carboxylic [1 4], sulfonic [5], phos-
phoric [6 9], phosphonic [10 13], and other acid
esters and halides [14 16] in terms of the extra-
a common opinion that just the neutral form of
hydroxylamine reacts with carboxylic, phosphoric,
and phosphonic esters and halides [22]; According to
Bruice and Benkovic [23], hydroxylamine in the
anionic form (NH2O ) usually does not react with
esters. However, proceeding from the definition of
-effect given in [22, 24], hydroxylamine meets all
requirements imposed to -nucleophiles. First, the
nucleophilic center therein is a negatively charged
2nd Row atom (oxygen). Second, there are no substit-
uents neighboring to the nucleophilic center, which
could exert steric hindrance to attack on electrophilic
center of a substrate. Third, the nucleophile contains
a catalytically active group (NH2) which is capable of
stabilizing transition states [25]. Finally, the electro-
negative nitrogen atom in the -position with respect
to the reaction center possesses an unshared electron
pair which can destabilize the ground state and
thermodynamic Bronsted relationship led to formula-
/
tion of the term -effect and discovery of a group
of -nucleophiles, including inorganic HOO , ClO ,
N3, etc. ions. Studies in the field of -effect and
design of new -nucleophiles intensely develop, as
follows from increasing number of recent publications
on this topic [17 21]. In this connection, hydroxyl-
amine anion attracts a specific interest. Hydroxyl-
amine is a parent compound for at least three typical
classes of anionic oxygen-containing -nucleophiles:
oximes, amidoximes, and hydroxamic acids, which
exhibit anomalously high reactivity in processes
involving acyl group transfer. Nevertheless, it is still
1070-4280/02/3809-1286$27.00 2002 MAIK Nauka/Interperiodica

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
1287
stabilize the transition state. In fact, we were the first
to demonstrate [26] that the anionic form of hydroxyl-
amine is responsible for a considerable acceleration
of acyl group transfer in alkaline media.
falls into the Bronsted plot for aroxide ions (Fig. 1a),
/
while in the reactions with esters II IV, positive
deviations from standard reaction series are as follows:
1
*
= 1.3, 4.7, 4.4 (Fig. 1b, 1c). In the reactions with
substrates II and III fluoride ion behaves like
an aroxide ion with pKa, calc = 5.4 and 11.1, whereas
The present article gives a detailed kinetic and
thermodynamic analysis of the behavior of hydroxyl-
amine and the most effective anionic oxygen-contain-
ing inorganic -nucleophiles, namely HOO , ClO ,
BrO , F and OH ions, in reactions with 4-nitro-
phenyl acetate (I), 4-nitrophenyl p-toluenesulfonate
(II), diethyl 4-nitrophenyl phosphate (III), ethyl
4-nitrophenyl ethylphosphonate (IV), and 4-nitro-
phenyl dimethylcarbamate (V) in water at 25 C at
a ionic strength of 1.0, which was maintained with
the aid of KCl.
The study was aimed primarily at establishing
reactive forms of hydroxylamine in acyl transfer
processes over a wide range of acidity of the medium,
quantitatively estimating the nucleophilic reactivity
of these forms in water, elucidating the reaction
mechanism, and, finally, revealing factors responsible
for the reactivity of hydroxylamine. It seemed to
be important to estimate the -effect for inorganic
-nucleophiles in acyl transfer processes and also to
analyze their relative nucleophilities in such reactions.
with ester IV it looks like an amine with pKa, calc
=
15.3 [36]. Analogous anomalies were also observed
in reactions of F with equatorial phosphoric triester,
2-(2,4-dinitrophenoxy)-1,3,2 5-dioxaphosphinane
2-oxide*2 (standard series: anionic oxygen-containing
nucleophiles,
phenyl methylphosphonate ion (standard series:
amines,
= 1.4, pKa, calc = 7.7)*3 [12], and 4-mor-
pholinopyridinium phosphate dianion (standard series:
anionic oxygen-containing nucleophiles, = 1.5,
= 3.9, pKa, calc = 9.1) [13], 4-nitro-
pKa, calc = 11) [37]. Fluoride ion is also more reactive
than ethoxide, phenoxide, and benzenethiolate ions
with respect to diisopropyl chlorophosphate*4 [38, 39].
Undoubtedly, the anomalously high nucleophilicity
of F in nucleophilic substitution at a four-coordinate
phosphorus atom, regardless of the charge on the
substrate and the nature of leaving group, indicates
____________
1
*
= logk2( -Nu)
logk2(Nu), where k2( -Nu) and k2(Nu)
are the second-order rate constants characterizing, respec-
tively, the reactivity of -nucleophile and a hypothetical
aroxide or alkoxide ion or amine for which pKa(Nu) =
pKa( -Nu).
Nucleophilic reactivity of fluoride ion. Attack by
F on the four-coordinate sulfur or phosphorus atom
in substrates II, III, and IV, as well as in I, leads to
formation of the corresponding acyl fluorides and
liberation of 4-nitrophenoxide ion. The reaction is
of first order with respect to both nucleophile and
substrate, and the rate of the process at pH = 8 9
(i.e., when the reagent exists only as fluoride ion) is
described by the following equation:
2
3
*
For the axial triester,
of and pKa,calc for the axial and equatorial triesters were
calculated from the data of [13].
= 3.4, pKa,calc = 10.3. The values
*
The values of
and pKa,calc were calculated using the
Bronsted equation logk = ( 7.30 0.18) + (0.31 0.02)
/
2
pKa for 18 amines. The pKa values of amines were measured
at 25 C (for details, see [37]).
4
*
Bunton and Shiner [40] give a pKHa F value of 4.77, while
pKa = 3 to 3.2 is given in [38, 39]. Insofar as in all cases the
nucleophilicity of F was estimated in alkaline media, the
difference in pKa cannot affect the second-order rate con-
stants. On the other hand, the positive deviations should
depend on pKa, but the qualitative pattern (Fig. 1a 1c) should
remain almost unchanged.
kap = k2 [F ] = k2 [NaF]0.
(1)
An unusual kinetic behavior of F toward electron-
deficient centers of the above substrates (carbon,
sulfur, and phosphorus atoms; see Table 1) should be
noted. The point for F ion in the reaction with ester I
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1288
SIMANENKO et al.
(a)
a strong affinity of F for the phosphoryl and phos-
phonoyl groups. A probable reason is the high stabil-
ity of fluorophosphates and fluorophosphonates [41]
due to resonance interactions both in the products and
in the transition states, which may be illustrated by
canonical structures A.
Such electronic interaction should exert a strong
stabilizing effect in the transition state, thus reducing
the energy barrier to the process. This assumption is
supported by the following experimental data. First,
fluoride ion exhibits an extremely low reactivity
toward a saturated carbon atom [39]; in nucleophilic
substitution at a saturated carbon atom, where no
resonance interactions like A occur, fluoride ion reacts
at a lower rate than do Cl , Br , and I , though its
basicity is greater by 10 to 14 orders of magnitude.
Second, the equilibrium constants Keq for the ex-
(b)
change reactions of F with isopropyl phenyl methyl-
phosphonates and isopropyl m-nitrophenyl methyl-
phosphonate are 300 and 2000, respectively [13];
extrapolation of Keq to a hypothetical phenol with
(c)
pKa pKHa F gives Keq = 5 105, i.e., the affinity of
F for the phosphonate group is greater by a factor
of 5 105 than the proton affinity of the hypothetical
aroxide ion. Finally, the high affinity of F for four-
coordinate phosphorus atom follows, on the one hand,
from the high rate of its reaction with 2-(2,4-dinitro-
5
phenoxy)-1,3,2 -dioxaphosphinane 2-oxide (the rate
constant corresponds to an aroxide ion with pKa 10)
and, on the other, from the low rate of hydrolysis of
the resulting phosphorus fluoride with water (the rate
of its hydrolysis is by 5 orders of magnitude lower,
as compared to a hypothetical aryl ester with a leaving
group whose basicity is equal to that of F .
Fig. 1. (a) Bronsted dependences for the reactions of
/
(1) aroxide ions and (2) -nucleophiles with 4-nitrophenyl
acetate (I); the data for aroxide ions were taken from [27];
VI, fluoride ion; VIII, hypochlorite ion; X, hydroperoxide
ion; XVI, hydroxylamine anion; XVII, hydroxylamine
Nucleophilic reactivity of hydroperoxide ion.
1
The rate of disappearance (kap, s ) of substrates II V
([S] = 1 M) in buffer solutions of hydrogen peroxide
linearly increases with rise in the analytical concentra-
tion of H2O2 and pH. However, the dependence of
(neutral). (b) Bronsted dependences for the reactions of
/
(1) aroxide ions and (2) -nucleophiles with 4-nitrophenyl
p-toluenesulfonate (II); the data for aroxide ions were
taken from [34]; VI, fluoride ion; VIII, hypochlorite ion;
IX, hypobromite ion; X, hydroperoxide ion; XVI, hydroxyl-
1
k2 = kap/[HOOH]0 (as well as of kap, s , at a con-
stant [HOOH]0) versus acidity of the medium is curvi-
linear, indicating that the reactive species is hydro-
peroxide ion. The rate of the process is described by
+
amine anion; XVII, hydroxylamine (neutral). (c) Bronsted
/
dependences for the reactions of (1) aroxide ions and
(2) -nucleophiles with diethyl 4-nitrophenyl phosphate
(III); the data for aroxide ions were taken from [35];
VI, fluoride ion; VIII, hypochlorite ion; IX, hypobromite
ion; X, hydroperoxide ion; XVI, hydroxylamine anion;
XVII, hydroxylamine (neutral).
Eq. (2), where
of HOO ion.
= Ka/(Ka + aH ) is the fraction
HOO
kap = k2 [HOOH]0 = k2
[HOOH]0.
(2)
HOO
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
1289
1
Table 1. Experimental conditions, basicities of nucleophiles (pKa), and their reactivities (k2, l mol 1 s ) toward
substrates I V; water, 25 C,
= 1.0 (KCl)
I
IIb
a
No.
Nucleophile
pKa
pH
k2
pH
k2
(3.4 0.6) 10
5
7
3
3
VI
F
3.18 [28]
15.7 [28]
1.05 10 [2]
14.4 [2]
8.00
c
VII
VIII
HO
ClO
12.0 13.5 (8.0 0.3) 10
11.75 (9.1 0.5) 10
7.4 0.1 (k)
7.5 (p) [28]
26.8 [2]
2
IX
X
BrO
8.7 [28]
8.99 12.29 (1.7 0.1) 10
11.00 12.69 0.99 0.01
HOO
11.5 0.1 (k)
11.6 [29]
4560 [2]
d
3
XI
CHF2CF2CH2O
(Me)3N CH2CH2O
CH3CH NO
CH3CONHO
CH3C(NH2)NO
NH2O
12.74 [30]
12.8 [31]
61 [33]
133 [33]
470 40
95 10
12.45 13.65 (5.8 0.1) 10
d
3
2
+
XII
XIII
XIV
XV
12.9 13.65 (4.00 0.05) 10
d
2
11.8 0.1 (k)
9.36 0.03 (p)
12.9 [9]
13.8 0.1e
13.74 [32]
7.82 9.00
7.00 8.20
10.3 12.8 (2.5 0.1) 10
d
8.4 11.5 (3.06 0.09) 10
d
2
35 5
10.0 13.19 (3.5 0.1) 10
XVI
9.50 10.66 36490 1960f
9.90 12.80 4.0 0.4
5
XVII NH2OH
6.09 0.05 (p)
6.0 10.66 1.41 0.21f
6.0 9.30 (2.50 0.25) 10
III
IV
V
No.
pH
k2
pH
k2
pH
k2
4
3
VI
8.0 9.0
(3.2 0.5) 10
(9.6 0.6) 10
(4.2 0.6) 10
8.00 11.0
10.0 13.0
(9.2 0.4) 10
0.15 0.01
3
3
4
4
VII
VIII
12.5 13.4
10.0 11.79
11.5 12.8
(5.6 0.1) 10
(1.8 0.4) 10
2
10.68 12.01
9.00 10.06
(6.8 0.4) 10
(7.2 0.9) 10
12.5 13.10
2 g
2
IX
11.0 12.0
10.8 12.5
12.5 13.0
12.9 13.3
10.8 12.8
8.4 11.5
(1.0 0.3) 10
0.55 0.02
11.20 11.50
11.05 12.50
11.98 13.00
11.50 12.65
9.0 10.5
0.15 0.04
2
X
7.3 0.8
10.5 12.8
(1.6 0.4) 10
2
2
2
XI
(5.7 0.1) 10
(2.4 0.2) 10
(2.5 0.2) 10
0.10 0.01
3
4
4
4
4
4
XII
XIII
XIV
XV
(1.75 0.15) 10
11.70 13.30
10.8 12.8
8.40 10.95
11.90 13.30
10.5 12.7
8.00
(3.2 0.1) 10
(2.4 0.2) 10
(4.9 0.4) 10
(1.9 0.1) 10
0.15 0.02
2
(1.1 0.1) 10
2
2
2
(2.3 0.3) 10
7.00 8.20
(4.1 0.6) 10
(4.1 0.6) 10
4.10 0.07
3
12.0 13.1
(2.9 0.1) 10
10.96 13.09
10.47 12.00
7.00 9.22
XVI 10.91 12.89
XVII 6.0 9.3
0.36 0.02
3
7
(1.90 0.15) 10
(1.1 0.1) 10
(7.5 0.7) 10
a
b
c
The acid ionization constants were determined by potentiometric (p) or kinetic (k) method.
The reactions of nucleophiles with ester III were studied in 5% aqueous ethanol.
14
The activity of hydroxide ion was estimated by the equation Kw = aH+ aOH = 10
.
d
For determination of kN2 H OH and kN2 H O , quantitative treatment of the experimental data was performed using the equation
2
2
k2/
= kN2 H OH + kN2 H O
/
.
2
2
NH OH
NH O
NH OH
2
2
2
e
f
Average pKa value; see text.
The reactivity of anions derived from 2,2,3,3-tetrafluoropropanol, choline, acetaldehyde oxime, acetohydroxamic acid, and acet-
amide oxime was determined using the equation kap = k2 [Nu ].
The reactivity of hypochlorite ion was estimated from the disappearance of ester IV ( 280 nm).
g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1290
SIMANENKO et al.
(kHOO /kCH OO
3
Transformation of Eq. (2) into (3) allows us to
30) [37] and 4-nitrophenyl methyl-
phosphonate monoanions (kHOO /kCH OO
50) [12],
3
calculate k2, which characterizes the nucleophilicity
of HOO ion, and acid ionization constant of the con-
jugate acid (Ka).
as well as with triacetylenediamine (kHOO /kCH OO
20) [42], is consistent with hydrogen bond formation
in transition states like B and C. However, the effect
of such assistance in reactions with aryl carboxylates
is likely to be insignificant, for the nucleophilicities
of HOO and CH3OO differ by a factor of only 3.
Therefore, it is improbable that general acid catalysis
(or the absence of it) is the only factor responsible
for supernucleophilic properties of hydroperoxide ion.
In fact, reactions of HOO with alkyl halides occur at
an anomalously high rate [22], though this kind of
catalysis does not play a significant role in alkyl
group transfer reactions. It is also unlikely that high
rates of acid-catalyzed addition of HOO ion to
aldehydes originate from formation of intramolecular
hydrogen bond in these processes [43].
3
1
+
k2 = k2
k2 aH Ka
.
(3)
5
*
The calculated values of k2 and pKa are given in
Table 1. A good agreement between the calculated
values and those reported in [28] indicates that only
nucleophilic attack by HOO ion on substrates II V
occurs, resulting in formation of the corresponding
peroxy acids.
Hydroperoxide ion as a typical -nucleophile
exhibits a high reactivity toward any electron-deficient
center, regardless of its nature (carbon, sulfur, or
phosphorus atom) [22]. Its behavior in reactions with
substrates I V is not an exception. The -effect in
the transfer of acetyl (I), p-toluenesulfonyl (II), and
It should be emphasized that the positive deviations
of F and HOO
phosphoryl (III) groups (kH2 OO /k2ArO ) is 22, 7.0 102,
and 9.1 102, respectively; in other words, HOO
reacts like aroxide ions with pKa, calc = 14.6, 16.4,
and 22.0, respectively. In the reaction with IV, hydro-
from standard reaction series
for processes involving transfer of phosphoryl (III)
and phosphonoyl groups (IV) are similar, though
fluoride ion is not an -nucleophile. Analogous
peroxide ion behaves like an amine with pKa, clac
=
Bronsted analysis of the kinetic behavior of normal
/
22.3, and the -effect is equal to 1.3 104. Even larger
pKa, calc value ( 28.0) was found for the reaction of
HOO with 4-morpholinopyridinium phosphate di-
anion; here, the -effect was estimated at 6 102 [37].
Naturally, the absolute value of -effect for HOO
ion, as well as for any other -nucleophile, depends
on the selected standard series. Nevertheless, it is
quite obvious that hydroperoxide ion is one of the
most powerful acyl group acceptors.
anionic oxygen-containing nucleophiles and F and
HOO ions gives comparable deviations for F and
HOO in reactions with 4-morpholinopyridinium
phosphate dianion (XVIII) [37]. On the other hand,
comparative analysis of the degree of bond dissocia-
tion ( lg) in the transition state and the stability of
transition states (logkXNuVIII) in reactions of the above
nucleophiles with substrate XVIII shows that the
dependence
XVIII
Nu
k
is linear. Therefore, an im-
lg
The anomalously high reactivity of hydroperoxide
ion in acyl group transfer processes is interpreted in
terms of general acid catalysis, i.e., assistance to
elimination of leaving group. Stabilization of transi-
tion states B and C via hydrogen bonding with
equatorial oxygen atom of the acyl group should favor
fast elimination of 4-nitrophenoxide ion in reactions
with esters I V.
portant role in the reactivity of HOO (as well as
of F , see above) is played by the stability of reaction
products and transition states; i.e., the nucleophilicity
of hydroperoxide ion is essentially controlled by
thermodynamic factor. Presumably, just intramole-
cular acid catalysis and relatively high thermodynamic
stability of transition states B and C are responsible
for the observed -effect of HOO ion in acyl group
transfer processes.
Nucleophilic reactivity of hypohalite ions. While
estimating the reactivity of ClO and BrO ions on
a quantitative level, it should be kept in mind that
these ions are efficient nucleophilic catalysts [2, 44]
and that their conjugate acids exhibit pronounced
oxidizing ability with respect to 4-nitrophenoxide ion.
The kinetic curves plotted in Fig. 2a illustrate varia-
tion of the absorption of 4-nitrophenoxide ion with
time at different pH in the reaction of ClO with ester
II. The ascending branches of the curves correspond
to accumulation of 4-nitrophenoxide ion in the system
The stronger nucleophilicity of HOO relative to
CH3OO in reactions with 4-nitrophenyl sulfate
____________
5
*
The value of Ka for hydrogen peroxide was determined as
an average of four Ka values obtained by treatment of the
kinetic data for all the substrates by Eq. (3).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
as a result of substrate dissociation, and the descend-
1291
(a)
ing branches correspond to its oxidation. Displace-
ment of the maxima, reduction of the time necessary
to reach the maximum, and decrease of Dmax with
rise in the acidity of the medium suggest a complex
mechanism of oxidation of 4-nitrophenoxide ion
(Fig. 2a). Study of oxidation of 4-nitrophenoxide ion
in buffer solutions at various pH values (Table 2) led
us to the following equation for the reaction rate:
+
,
kap = kox [HHlgO] aH
(4)
where [HHlgO] is the equilibrium concentration of
the corresponding hypohalic acid. Treatment of the
experimental data (Table 2) according to Eq. (5):
(b)
+
,
kap/[HHlgO]0 = kox HHlgO aH
(5)
where
is the fraction of the conjugate acid,
HHlgO
gives the following third-order rate constants kox:
HClO
ox
1
HBrO
=
ox
k
= (9.15 0.35) 107 l2 mol 2 s and k
(5.20 0.09) 1010 l2 mol 2 s 1 (Fig. 2b). The obtained
experimental data convincingly indicate that the reac-
tion with ClO and BrO ions is a stepwise process
which is characterized by change of the rate-determin-
ing stage on variation of the acidity of the medium.
Fig. 2. (a) Change of the optical density ( 440 nm) with
time in the reaction of hypochlorite ion with 4-nitrophenyl
p-toluenesulfonate (II); water, 25 C,
[HClO]0 = 0.034 M, [II]0 = 4 10 M. (b) Plots of the
= 1.0 (KCl),
5
ox
ap
apparent second-order rate constants k /[HHlgO]0,
l mol 1 s, versus HHlgO aH+, M, for the oxidation of 4-nitro-
phenoxide ion with hypohalic acids.
following the disappearance of ester IV. The fact that
k2 values determined under different conditions
(Table 1) are similar indicates validity of the above
scheme.
Hypohalite ions (ClO - and BrO ) react with all
the examined substrates at an anomalously high rate.
In the first stage, attack by HlgO ion on the elec-
tron-deficient center of the substrate yields 4-nitro-
phenoxide ion and acyl hypohalite. The latter under-
goes fast hydrolysis with regeneration of HlgO . In
the second stage, 4-nitrophenoxide ion is oxidized
with hypohalic acid. If the oxidation of 4-nitrophen-
oxide ion is slow, it is possible to determine the
nucleophilic reactivity of ClO (9.4 pH 11.5) and
BrO ions (11.0 pH 12.0) in a usual way (Table 1).
The positive deviations of points from the Bronsted
/
dependences for standard reaction series (Fig. 1a 1c)
are (ClO ) = 3.2 3.6 and (BrO ) = 2.7 3.5, and
their nucleophilicities are comparable with the reac-
tivity of hypothetical nucleophiles with pKa, calc
=
kap = k2[HlgO ].
(6)
11.6 18.8. It should be noted that the positive devia-
tions are very similar and are almost independent on
the substrate nature, i.e., BrO and ClO ions exhibit
properties typical of -nucleophiles. Probably, the
-effect for hypohalite ions originates from formation
of such rate-determining transition state in which the
The reactivity of ClO ion can also be estimated
quantitatively using Eq. (7) at such pH values when
the rate of oxidation of 4-nitrophenoxide ion is much
higher than the rate of the reaction of ClO with ester
IV, provided that the reaction course is monitored
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1292
SIMANENKO et al.
Table 2. Experimental conditions and apparent pseudo-
first-order rate constants for the oxidation of 4-nitrophen-
oxide ion with hypohalic acids at 25 C, = 1.0 (KCl)
weakly sensitive to the ionic strength, and the acid
base components of TRIS, acetate, phosphate, car-
bonate, 4-aminopyridine, and imidazole buffers almost
do not affect the apparent second-order rate constants
1
HClO
HBrO
k2 = (kap kOH aOH )/[NH2OH]0, l mol 1 s , of these
processes (Fig. 3). The reactions are of an overall
second order: first in hydroxylamine and first in the
substrate; these orders do not change throughout the
examined pH range (Fig. 4a).
[HClO]0,
M
[HBrO]0,
M
1
1
pHa kap, s
pHa
kap, s
6.95 0.041
7.07 0.027
7.27 0.013
7.48 0.015
7.42 0.014
7.86 0.0037
8.08 0.0015
0.005
0.005
0.005
0.01
0.01
0.01
8.99 0.154
9.22 0.0617
9.44 0.0272
9.57 0.0163
9.95 0.0106
10.02 0.0078
0.0066
0.0024
10.55 0.0016
0.00747
0.00747
0.00747
0.00747
0.016
0.016
0.016
0.016
0.016
On the other hand, the pH profiles obtained for
the above processes differ considerably from those
observed for substrate I [2], 4-nitrophenyl methyl-
phosphonate [12], etc. [45]. As pH increases, the rate
of the reaction of hydroxylamine with the examined
substrates (logk2) rapidly comes to a plateau (even
at pH 7.0); pH-independent acyl group transfer then
occurs; and, beginning with pH 9.0, the reaction rate
again increases as the acidity of the medium falls
down (Fig. 4b). In the pH range from 10.4 to 12.9,
the rate of transfer of p-tolylsulfonyl, diethoxyphos-
phinoyl, ethoxy(ethyl)phosphinoyl, and dimethylcar-
bamoyl groups is linearly related to pH [Eq. (7)].
0.01
10.2
10.4
a
The required pH values were maintained using a solution of
sodium carbonate ([Na2CO3]0 = 0.02 M) in the case of hypo-
bromous acid and a solution of sodium phosphate ([Na3PO4]0 =
0.02 M) in the case of hypochlorous acid.
logk2(II) = (13.08 0.16) + (0.99 0.01)pH; (7)
n = 10, s = 0.035, r = 0.99.
acyl oxygen atom interacts with vacant d-orbitals of
hypohalite ion. In essence, hypohalite ions as Lewis
acids are capable of assisting acyl transfer in the same
The same tendency in the character of pH effect
on the reaction rate is observed in the reaction of
hydroxylamine with ester I at pH = 9.6 10.8. Finally,
the pH profiles for the reactions with compounds II,
III, and V show one more bend at relatively high
concentrations of hydroxide ion, and logk2 attains its
maximal value (logk2, max) at [OH ] 2 M (Fig. 4b).
We were the first to reveal such an unusual behavior
of hydroxylamine toward substrates having different
electrophilic centers (unsaturated carbon, sulfur, and
phosphorus atoms) on variation of the acidity of the
medium over a wide range.
manner as do Bronsted acids.
Nucleophilic reactivity of hydroxylamine. Reac-
tions of hydroxylamine with the esters under study are
/
The similarity of the pH profiles for the examined
esters suggests that the observed pattern should be
interpreted in terms of hydroxylamine properties. The
latter in aqueous s+olution can exist in the following
forms: cationic (NH3OH), neutral (NH2OH), and
anionic (NH2O ) (see scheme below); two of these,
NH2OH and NH2O , can act as O-nucleophile.
Fig. 3. Semilog plots of the rate constants (logk2) for the
reaction of hydroxylamine with 4-nitrophenyl p-toluenesul-
fonate (II) versus buffer concentration: (1) imidazole
buffer, pH = 12.75; (2) phosphate buffer, pH = 12.20;
(3) piperidine buffer, pH = 11.00; (4) carbonate buffer,
pH = 9.50; (5) 4-aminopyridine buffer, pH = 9.45; (6) TRIS
buffer, pH = 9.00; water, 25 C,
= 1.0 (KCl).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
In the region of pH-independent acyl group
1293
(a)
transfer, where only the neutral form of hydroxyl-
amine reacts with the substrate and its fraction
NH2OH
tends to unity, the value of kN2 H OH may be determined
2
from any point lying on the plateau of the pH-profile,
since k2 = kN2 H OH. In the acidity range corresponding
2
to 0.9 >
> 0.1, the kinetic data were treated
NH2OH
according to the formula k2 = kN2 H OH NH OH. Table 1
2
2
contains the average values for esters I V derived
from 12 16 measurements for each substrate.
The situation in alkaline media is less clear. A con-
siderable increase (by 3 to 5 orders of magnitude) of
the rate of acyl group group transfer may result from
(1) general base catalysis by hydroxide ion (a kinetic
equivalent is specific base catalysis and general acid
catalysis with water) of the reaction of hydroxylamine
with the substrates under study [Eq. (8)] and (2) SN2
reaction involving nucleophilic attack on the substrate
by the oxygen atom of NH2O [Eq. (9)].
(b)
+
aH
k2 = kN3 H OH NH OH [OH]0 =
kN3 H OH [OH]0;
2
2
2
+
Ka2 + aH
(8)
Ka2
k2 = kN2 H O
=
kN2 H O
.
(9)
2
2
NH2O
+
Ka2 + aH
There is a simple relation between the above
kinetic expressions:
kN2 H O = k3NH OH(Kw/Ka2);
2
2
Fig. 4. (a) Dependences of the appearent pseudofirst-order
rate constants kap, s , for the reaction of hydroxylamine
1
with 4-nitrophenyl p-toluenesulfonate (II) versus initial
hydroxylamine concentration [NH2OH]0 at different pH;
5% aqueous ethanol, 25 C, = 1.0 (KCl). (b) pH-Profiles
for the reactions of hydroxylamine with 4-nitrophenyl
acetate (I), 4-nitrophenyl p-toluenesulfonate (II), diethyl
4-nitrophenyl phosphate (III), ethyl 4-nitrophenyl ethyl-
phosphonate (IV), and 4-nitrophenyl dimethylcarbamate
therefore, the two mechanisms are kinetically indis-
tinguishable. On the basis of formal kinetic analysis
it is impossible to determine which form of hydroxyl-
amine is responsible for acyl group transfer at
pH 10. Nevertheless, we prefer Eq. (9) rather than
(8), i.e., O-nucleophilic attack by NH2O on the elec-
tron-deficient center of the substrate (SN2 reaction).
Kinetic expression (8) implies a stepwise mechanism
of acyl group transfer [38] with formation of a fairly
stable intermediate, zwitterionic, neutral, or anionic.
It is hardly probable for substrates II IV since the
corresponding five-coordinate intermediates having
a bipyramidal structure should be characterized by
a lifetime approaching the duration of the activation
act [46]. Furthermore, for none of the examined
substrates we observed promoting effect of acid base
buffer components (Fig. 3), though such an effect is
rather a rule than an exception for systems involving
acid base catalysis [47]. Reactions of substrates I and
II, III and IV with common nucleophiles, such as
(V); water, 25 C,
= 1.0 (KCl).
aroxide, alkoxide, and hydroxide ions, and with
a number of typical -nucleophiles, such as anions
derived from acetamide oxime, acetaldehyde oxime,
acetohydroxamic acid, hydrogen peroxide, and hypo-
halic acids, fit linear correlations (10)*6 and (11)
which interrelate activation barriers to transfer of
p-tolylsulfonyl and acetyl, diethoxyphosphinoyl and
ethoxy(ethyl)phosphinoyl groups to a fixed anionic
oxygen-containing nucleophile (Fig. 5). These correla-
____________
6
*
While building up correlation (10), the data for fluoride ion
were not taken into account.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1294
SIMANENKO et al.
A good agreement between the acid ionization con-
stants determined by the kinetic titration technique
and pKa2 = 13.74 found by spectrophotometry [32]
is unlikely to be accidental. Most probably, the above
data directly indicate the absence of general acid base
catalysis by the Bronsted pair OH H O of hydroxyl-
/
2
amine reactions at pH > 10. Another conclusion is
that the limiting values of apparent second-order rate
constants at [OH ]0 > 1 M for substrates II, III, and
V characterize just the nucleophilicity of NH2O ion,
i.e., k2, max = kN2 H O . Thus the pH-profiles for the
2
reactions of hydroxylamine with substrates II, III, and
V are correctly interpreted in terms of the proposed
reaction scheme (see above) and the rate of acyl group
transfer to the neutral and anionic forms of hydroxyl-
amine is described by Eq. (13):
Fig. 5. Correlation between the rate constants of the reac-
kap = kN2 H OH [NH2OH] + k2NH O [NH2O ]. (13)
2
2
tions of various O-nucleophiles with 4-nitrophenyl acetate
(I) and 4-nitrophenyl p-toluenesulfonate (II). Nucleophiles:
VI, fluoride ion; VII, hydroxide ion; VIII, hypochlorite
ion; X, hydroperoxide ion; XI, 2,2,3,3-tetrafluoropropanol;
XII, choline; XIII, acetaldehyde oximate ion; XIV, aceto-
hydroxamate ion; XV, acetamide oximate ion; XVI, hy-
droxylamine anion; XIX, phenol; XX, pentafluorophenol;
XXI, 4-chlorophenol; XXII, 4-methoxyphenol; XXIII,
2,2,2-trifluoroethanol; XXIV, 2-propynyl alcohol. The data
for compounds XIX XXIV were taken from [2, 33, 34].
Comparative analysis of the reactivity of in-
organic -nucleophiles. Hydroxylamine occupies
a specific place among inorganic oxygen-containing
anionic -nucleophiles, for it is the only compound
which in aqueous solution gives rise to two reactive
O-nucleophilic species, NH2OH and NH2O . The
basicities of these forms differ very strongly, by about
16 orders of magnitude (Table 1). This difference may
be compared only with the difference in the basicities
of oxygen in a neutral water molecule and hydroxide
ion. The differences in the kinetic behavior of NH2OH
and NH2O are also surprising.
tions cover the range of nucleophilic substitution rates
of about 7 orders of magnitude for the pair II I
[Eq. (10)] and 4 orders of magnitude for the pair
III IV [Eq. (11)]. The data for hydroxylamine anion
are also included.
The positive deviations for NH2O ion from stand-
ard reaction series are as follows: = 1.5 (I), 2.1 (II),
1.5 (III), and 1.0 (IV). However, it is much more
important that the reactivity of hydroxylamine anion
toward esters I, II, and V exceeds the reactivity of one
of the most powerful -nucleophiles, hydroperoxide
logkI2 = (3.87 0.13) + (1.02 0.06)logkI2I; (10)
n = 15, r = 0.96;
logkI2V = (1.00 0.14) + (0.98 0.06) logkI2II
n = 12, r = 0.97.
;
(11)
ion, by a factor (kN2 H O /k2HOO ) of 8, 4, and ~10,
2
respectively (Table 1). In the reactions with III and
IV, the nucleophilicities of HOO - and NH2O are
comparable. Undoubtedly, NH2O is the most power-
ful acyl group acceptor, so that there are all grounds
to rank it first in the series of -nucleophiles.
Bronsted dependences (14) (16) are fulfilled for
/
the reactions of inorganic -nucleophiles with esters
Finally, the following should be noted: treatment
of a large array of kinetic data ( 20 values of k2, pH
range 10 13.5) for each substrate II, III, and V by
Eq. (12) with account taken of the limiting values of
k2 = k2, max gave pKa2 values for hydroxylamine equal
to 13.83 0.11, 13.79 0.09, and 13.81 0.08, respec-
tively.
I, II, and V:
logkI2 = ( 2.2 0.4) + (0.50 0.04)pKa;
n = 3, r = 0.99;
(14)
(15)
pKa2 = pH + log[(1
)/
]. (12)
NH2O
NH2O
Here, values were calculated by the formula
A
logkI2I = ( 5.5 0.6) + (0.45 0.06)pKa;
n = 4, r = 0.97;
= k2/k2, max
.
A
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
1295
logkV2 = ( 7.2 0.1) + (0.46 0.01)pKa;
n = 3, r = 0.99.
(16)
study it reacts like hypothetical -nucleophiles with
pKa 1 5 (Fig. 1a 1c). In fact, these data suggest
that the mechanism of acyl group transfer to NH2OH
radically differs from the mechanism typical of
inorganic -nucleophiles. On the basis of kinetic
isotope effects, Hess et al. [3] recently proposed the
following mechanism for the reaction of hydroxyl-
amine with 4-nitrophenyl acetate (I). In the first
reversible stage (which involves general base assist-
ance by the amino group of hydroxylamine), zwitter-
ionic tetrahedral addition product D is formed.
Two hydrogen atoms of the amino group in D form
intramolecular hydrogen bond with the carbonyl
oxygen atom:
Hence the basicity is among factors determining
the nucleophilicity of inorganic anionic -nucleo-
philes. The basicity of esters III and IV also controls
the rate of transfer of diethoxyphosphinoyl and
ethoxy(ethyl)phosphinoyl groups [Eqs. (17), (18)], but
the points for HOO are characterized by positive
deviations: (III) = 0.94, (IV) = 0.93. A probable
reason is that their reactions involve intramolecular
general acid catalysis (see structure B above). Prob-
ably, here we observe enhanced reactivity of HOO
rather than reduced reactivity of NH2O .
logkI2II = ( 4.4 0.1) + (0.28 0.01)pKa; (17)
n = 4, r = 0.99;
logkI2V = ( 2.9 0.2) + (0.25 0.02)pKa;
n = 4, r = 0.99.
(18)
In the rate-determining stage (under conditions of
general acid catalysis), intermediate D slowly decom-
poses to give O-acetylhydroxylamine. Naturally, the
occurrence of general acid base assistance is crucial
for understanding a number of aspects of the kinetic
behavior of such weakly basic O-nucleophile as
hydroxylamine. Nevertheless, the proposed O-acyla-
tion mechanism remains questionable, for it can
explain neither the behavior of N,N-dialkylhydroxyl-
amines in the same reaction nor the existence of
An additional support to the above stated is given
by the fact that HOO and NH2O ions fit linear
dependences (10) and (11) which interrelate stabilities
of transition states in the reactions of common nucleo-
philes and -nucleophiles with substrates I/II and
III/IV (Fig. 5). An important role of the thermo-
dynamic factor in the reactivity of nucleophiles is also
indicated by the following. The Bronsted dependences
/
for -nucleophiles reacting with esters III and IV
(Fig. 1c) include the point for fluoride ion, though the
latter is not an -nucleophile; in the case of esters I
and II (Fig. 1a, 1b), the points for fluoride ion show
appreciable negative deviations: (I) = 4.2 and
(II) = 2.4. Presumably, the existence of correlations
(10) and (11) provides an additional support to the
assumption that thermodynamical stability of transi-
tion states is an important factor responsible for the
reactivity of not only common nucleophiles but also
-nucleophiles.
a single Bronsted dependence for the reactions of
/
hydroxylamine and its N-alkyl- and N,N-dialkyl
derivatives with substrate I [48]. Presumably, unlike
the mechanism including formation of zwitterionic
intermediate D, the acylation of hydroxylamine
involves cyclic transition states like E G. A necessary
and sufficient condition is that only the hydroxy
The kinetic behavior of neutral hydroxylamine
species in acyl group transfer processes seems to be
even more surprising. The points for NH2OH show
considerable positive deviations not only from stand-
ard reaction series [ (I) 9.0, (II) 6.0, (III)
6.0, (IV)
6.1] but also from Bronsted relations
/
(14) (18) for -nucleophiles [ (I) 3.4, (II) 1.8,
(III) 1.6, (IV) 0.5, (V) 2.0] (Fig. 1a 1c).
Obviously, the neutral form of hydroxylamine exhibits
an anomalously high reactivity even among the series
of inorganic -nucleophiles; with the substrates under
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1296
SIMANENKO et al.
hydrogen atom of hydroxylamine should participate
in hydrogen bonding. The presence of an amine-like
form of hydroxylamine in transition states E G, as
well as general acid base assistance, should reduce
the energy barrier and hence should favor high rates
of acyl group transfer to both hydroxylamine and its
N-alkyl and N,N-dialkyl derivatives.
To conclude, let us emphasize once more that
hydroxylamine is a unique -nucleophile whose
neutral and anionic forms ensure high rates of acyl
group transfer throughout a wide pH range. None of
the known -nucleophiles can compete with hydroxyl-
amine in this respect.
reactants were prepared just before each series
of kinetic experiments, and their concentrations were
selected in such a way that they also act as buffer
components. If the initial nucleophile concentration
was less than 0.02 M, the acidity of the medium was
maintained with the aid of potassium phosphate
(pH 6.0 7.5), tris(hydroxymethyl)aminomethane
(TRIS, pH 7.5 9.0), and sodium carbonate (pH 9.0
11.5) at a concentration of 0.1 0.05 M. Buffer solu-
tions were adjusted to a required pH value by adding
a concentrated solution of KOH or HCl. The acidity
of the medium was checked both before and after each
kinetic experiments; if the difference in the initial and
final pH values was greater than 0.05, the data were
rejected. The ionic strength ( = 1.0) was maintained
with potassium chloride. The concentration of hydro-
gen peroxide, hypochlorous acid, and hypobromous
acid was determined by permanganatometric and iodo-
metric titration, and ionic strength was then fixed
at = 1.0. In alkaline medium hydroxylamine can be
oxidized by oxygen dissolved in water [32]. Prior to
kinetic studies, by special experiments we showed that
hydroxylamine solutions (pH 10 13) prepared both
in air and under argon showed the same reactivity.
EXPERIMENTAL
Substrates I V were synthesized by acylation of
4-nitrophenol with acetic anhydride, p-toluenesulfonyl
chloride, diethyl chlorophosphate, ethyl ethylchloro-
phosphonate, and dimethylcarbamoyl chloride, respec-
tively, in dry dioxane in the presence of triethylamine.
After isolation, ester I was purified by double recrys-
tallization from hexane, and esters II and V were
recrystallized thrice from anhydrous ethanol. Esters
III and IV were doubly distilled under reduced pres-
sure (0.05 mm). The physical constants of compounds
I V (melting points and n2D0 values) and their UV
spectra were in full agreement with published data.
Hydroxylamine hydrochloride was thrice recrystal-
lized from ethanol, mp 159 C (decomp.); the purity
of NH2OH HCl was checked by titration with potas-
sium bromate [49]. Acetohydroxamic acid was syn-
thesized by the procedure reported in [50] and was
purified by triple recrystallization from anhydrous
ethanol, mp 92 C. Acetamide oxime was prepared as
described in [51]; it was repeatedly crystallized from
butanol until constant melting point, mp 135 C. Acet-
aldehyde oxime and 2,2,3,3-tetrafluoropropanol were
purified by standard procedures. Choline chloride
(Sigma) was used without additional purification.
Hypochlorous acid containing no Cl2 and Cl was syn-
thesized according to the following scheme:
All experiments were performed in water or 5%
aqueous ethanol (for substrate II) at 25 C. Doubly
distilled water and anhydrous ethanol were used. In
the kinetic experiments, the initial substrate concentra-
5
tion ([S]0 5 10 M) was much less than the initial
nucleophile concentration, and the apparent pseudo-
1
first-order rate constants (kap, s ) remained constant
up to six half-conversion periods of the sustrate. The
1
values of kap, s , were determined from the change
in the optical density using the equation
ln(D
D ) = ln(D
D0)
kap ,
where D0, D , and D are the optical densities at = 0
(reaction start), 1, and after reaction completion.
=
1
As a rule, the apparent rate constants kap, s , were
corrected for the contribution of alkaline hydrolysis
provided that it was more than 5% of kap; i.e., kap
=
kap kOH aOH. The rate constants of alkaline hydrol-
ysis kOH, l mol 1 s , for the substrates under study
were determined independently on the basis of the
activity of hydroxide ion in water at 25 C ( = 1.0);
their values are given in Table 1.
The acid ionization constants of hydroxylamine,
acetamide oxime, and acetohydroxamic acid in 5%
aqueous ethanol ( = 1.0) at 25 C were determined
by potentiometric titration (Table 1) with 0.1 M KOH
or HCl. The pKa values were calculated by the
1
Hypobromous acid was prepared by adding
bromine to water in a dropwise manner [52]. In-
organic reagents of ultrapure or chemically pure grade
were not subjected to additional purification.
The procedure for kinetic measurements was de-
scribed in detail in [5, 34]. The progress of reactions
was monitored following the absorption of liberated
4-nitrophenoxide ion ( 400 440 nm). Solutions of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

INORGANIC ANIONIC OXYGEN-CONTAINING -NUCLEOPHILES
1297
Henderson Hasselbach equation [28]. The pKa values
for ClO and HOO were determined from the kinetic
measurements.
18. Hoz, S., Liu, P., and Buncel, E., J. Chem. Soc.,
Chem. Commun., 1996, pp. 995 996.
19. Terrier, F., Dagorre, F., Kiffer, D., and Laloi, M.,
Bull. Soc. Chim. Fr., 1988, no. 2, pp. 415 419.
The errors in determination of pKa were estimated
by small sample statistics; linear correlations were
treated by the least-squares procedure.
20. Terrier, F., MacCormack, P., Kizilian, E.,
Halle, J.-C., Demerseman, P., Guir, F., and
Lion, C.J., J. Chem. Soc., Perkin Trans. 2, 1991,
no. 1, pp. 153 158.
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