Predominant role of basicity of leaving group in α-effect for nucleophilic ester cleavage

Article abstract of DOI:10.1016/j.bioorg.2003.09.003

It has been found that α-effects in nucleophilic reactions, unexpectedly large nucleophilicity due to adjacent unpaired electrons, are strongly dependent on the structure of substrate. The nucleophilic cleavages of 4-nitrobenzoate esters and 4-methylbenzo

Full text of DOI:10.1016/j.bioorg.2003.09.003

BIOORGANIC
CHEMISTRY
Bioorganic Chemistry 32 (2004) 26–37
www.elsevier.com/locate/bioorg
Predominant role of basicity of leaving group
in a-effect for nucleophilic ester cleavage
Yasuo Nomura,a,b Takayasu Kubozono,b Makoto Hidaka,b
Mineko Horibe,b Naoki Mizushima,b Nobuyuki Yamamoto,b
Toshio Takahashi,b and Makoto Komiyamaa,*
a
Research Center for Advanced Science and Technology, The University of Tokyo,
4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
b
Lion Corporation, 13-12, Hirai 7-chome, Edogawa-ku, Tokyo 132-0035, Japan
Received 11 July 2003
Abstract
It has been found that a-effects in nucleophilic reactions, unexpectedly large nucleophilicity
due to adjacent unpaired electrons, are strongly dependent on the structure of substrate. The
nucleophilic cleavages of 4-nitrobenzoate esters and 4-methylbenzoate esters by HOOꢀ have
been systematically investigated in detail. When the leaving groups of substrates are suffi-
ciently good (aryl, 2,2,2-trifluoroethyl, and 2,2-dichloroethyl esters), a-effect is evident. How-
ever, this effect drastically decreases as the leaving group gets poorer, and is only marginal for
the cleavages of 2-fluoroethyl and methyl esters. In the nucleophilic cleavages by salicyl-
aldoxime and acetohydroxamic acid, a-effect is also notable only for the esters having
good leaving groups. These enormous dependences of a-effects on the substrate-structure have
been interpreted in terms of the difference in the position of transition-state in the reaction
coordinate.
Ó 2003 Elsevier Inc. All rights reserved.
Keywords: a-Effect; Nucleophilic ester cleavage; 4-Nitrobenzoate ester; 4-Methylbenzoate ester; Hydro-
peroxide ion; Hydroxyl ion; Rate constant; Substrate-structure; Transition-state; Reaction coordinate
* Corresponding author. Fax: +81-3-5452-5209.
E-mail address: komiyama@mkomi.rcast.u-tokyo.ac.jp (M. Komiyama).
0045-2068/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2003.09.003

Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
27
1. Introduction
Design of highly active nucleophilic agents is one of the keys for further develop-
ments of chemistry and biochemistry, and so-called ‘‘a-effect’’ has been widely em-
ployed there as the leading principle [1–4]. This interesting and significant proposal
in nucleophilic reactions says that ‘‘compounds which contain an electronegative
atom with a free electron pair adjacent to the nucleophilic atom display an unusually
high nucleophilic reactivity’’ [1]. One of the most comprehensive and conclusive data
supporting this hypothesis was presented by Jencks and Carriuolo [5] in the nucleo-
philic cleavages of 4-nitrophenyl acetate. Although the nucleophilicity of most of nu-
cleophiles monotonously increased with increasing pKa (as expected from Brønsted
law), the points for hydroperoxide ion, hydrazine, hydroxylamine and others, which
have adjacent unpaired electrons, significantly deviated from this relationship in
positive direction. For certain nucleophiles, the deviation was as large as 103- to
104-fold. Similar unusual rate enhancements assignable to a-effect were reported by
Bruice et al. [6] for the cleavage of phenyl acetate. Strong and concrete evidence for
‘‘a-effect’’ was provided. This effect is also significant in biological systems. For exam-
ple, hydroxylamine and hydrazine attack nucleobases in DNA far more efficiently
than does ammonia, resulting in the transformation of DNA to non-natural form [7].
Although many attempts have been made to rationalize a-effects in terms of phys-
icochemical factors (e.g., polarizability, hydrogen bonding, single electron transfer
character, and others), mechanistic details have not yet been sufficiently clear
[1–6,8–10]. Furthermore, it is uncertain if these effects are widely applicable to variety
of reactions involving non-activated substrates or not (because of experimental con-
venience, previous evidence for these effects was obtained only on the cleavages of
highly active aryl esters). In order to design highly active nucleophilic reactions by
using this effect, these points must be more clarified. Here we report the results of sys-
tematic studies on nucleophilic cleavages of 4-nitro- and 4-methylbenzoate esters
bearing various (both aryl and alkyl) leaving groups. As ‘‘a-effect’’ nucleophiles,
hydrogen peroxide and others are used. It will be shown that a-effect is dominant only
in the cleavages of the substrates having good leaving groups and marginal for the
cleavages of common alkyl esters. The role of the acyl portions of esters is also inves-
tigated. The origin of these remarkable substrate dependences of a-effect is discussed.
2. Materials and methods
2.1. Materials
Most of the ester substrates were prepared from the acid chloride and the alcohol,
and were sufficiently characterized by 1H NMR. The choline esters were obtained by
methylating the corresponding N,N-dimethylaminoethyl esters with dimethyl sulfate
[11]. Hydrogen peroxide was purchased from Mitsubishi Gas Company, INC and
used without further purification. The concentration of H2O2 therein was determined
by the titration with permanganate. The water used for the kinetic analysis was

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Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
purified by a Millipore Milli-XQ system, and has the specific resistance greater than
18.3 M X cmꢀ1. All other reagents were commercially obtained.
2.2. Kinetic analysis of ester cleavage
The reactions were initiated by adding stock solutions of esters (either in acetoni-
trile or in water), and carried out at 30 °C in 0.05 mol dmꢀ3 carbonate buffer (for the
reactions at pH 9.0) or 0.05 mol dmꢀ3 phosphate buffer (pH 6.0, 7.0, and 8.0). Ionic
strength was maintained at 0.1 mol dmꢀ3 by using NaCl. The substrate concentration
was 0.5 mmol dmꢀ3, and the concentration of hydrogen peroxide was varied in 5–
400 mmol dmꢀ3. With appropriate intervals, some portions of the reaction mixtures
were taken out and analyzed by the reversed-phase HPLC equipped with an RP-C18
column (Cica-Merck LiChroCART 125-4). The peaks were assigned by coinjection
with authentic samples. By using the absorbance at 260 nm, the amounts of ester,
acid, and alcohol (only for the aryl esters) were determined. In all the reactions,
the disappearance of ester satisfactorily showed pseudo-first-order kinetics. The per-
acids (R1C(O)OOH), formed by the nucleophilic attack of HOOꢀ towards the car-
bonyl carbon atom of R1C(O)OR2, were rapidly digested to the acids under the
conditions employed and not much accumulated.
The kinetic behaviors of ester cleavages are summarized as follows:
(1) In the absence of hydrogen peroxide, the apparent first-order rate constant kobs
for the disappearance of ester was proportional to [HOꢀ].
(2) At constant pH, kobs increased in proportional to [HOOH]0.
(3) The slope of linear plot between kobs and the equilibrium concentrations of
HOOꢀ in the mixtures was constant irrespective of pH. Here, [HOOꢀ] was cal-
culated by using pKa of HOOH (11.6) [12]. On the basis of these results, kobs is
expressed by Eq. (1):
kobs ¼ k1½HOOꢀꢁ þ k2½OHꢀꢁ þ k3;
ð1Þ
where k1 and k2 are the second-order rate constants for the nucleophilic cleavages of
ester by HOOꢀ and HOꢀ, respectively, and k3 is the first-order rate constant for the
water reaction. Buffer catalysis is negligibly small in the present reactions, as con-
firmed by control experiments. The rate constants for the ester cleavages by other
nucleophiles were determined in the same way.
3. Results and discussion
3.1. Hydrogen peroxide for nucleophilic cleavages of 4-nitro- and 4-methylbenzoate
esters having various leaving groups
When hydrogen peroxide was added to aqueous solutions of aryl and alkyl esters
of 4-nitrobenzoate and 4-methylbenzoate in Table 1, the cleavages of these esters
were significantly accelerated with respect to the reactions in its absence. The pseu-
do-first-order rate constants were proportional to the concentration of hydrogen

Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
29
Table 1
Structures of esters used and the pKa of conjugate acids of their leaving groups
a
pKa
4-Nitrobenzoate esters
Aryl esters
(1)
8.66
9.46
(2)
(3)
10.3
Alkyl esters
(4)
12.4
12.9
13.2
14.4
15.5
(5)
(6)
(7)
(8)
4-Methylbenzoate esters
Aryl esters
(9)
8.66
(10)
(11)
9.90
10.3

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Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
Table 1 (continued)
a
pKa
Alkyl esters
(12)
12.4
12.9
13.2
(13)
(14)
a Ref. [12].
peroxide. Furthermore, the logarithm of rate linearly increased with the pH of solu-
tion, and the slope of this straight line was unity. Apparently, the ester cleavages by
hydrogen peroxide proceed with HOOꢀ as the nucleophilic species (the pKa of
HOOH is 11.6) [12,13]. All the second-order rate constants k1 for the ester cleavage
by HOOꢀ are listed in Table 2. The rate constants k2 for alkaline hydrolysis of these
esters, determined by the pH dependence of hydrolysis rate in the absence of hydro-
gen peroxide, are also presented.
As shown in Fig. 1A, the k1 for the cleavages of aryl esters of 4-nitrobenzoate by
HOOꢀ (the open circles) monotonously decreases with increasing pKa of the conju-
gate acid of leaving group. On the other hand, the k1 values for the cleavages of alkyl
esters by HOOꢀ (the closed circles) fit another straight line, which is much steeper
than that for the aryl esters (the slopes are )0.8 and )1.5, respectively: see Table 3).
Table 2
Second-order rate constants k1 and k2 (in sꢀ1 molꢀ1 dm3) for the cleavage of various benzoate esters by
HOOꢀ (k1) and by HOꢀ (k2)
Ester
k1 (sꢀ1 molꢀ1 dm3)
k2 (sꢀ1 molꢀ1 dm3)
(1)
(2)
14,000
1700
800
600
80
25
8
(3)
(4)
6
45
15
9
(5)
(6)
8
(7)
(8)
0.2
0.02
200
30
9
3
(9)
0.2
0.6
0.08
1.8
0.2
1.6
(10)
(11)
(12)
(13)
(14)
10
20
0.6
0.4
(The structures of esters are presented in Table 1 in text.)

Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
31
Fig. 1. Plots of the second-order rate constants k1 at 30 °C for the HOOꢀ-induced cleavages of (A) 4-ni-
trobenzoate esters and (B) 4-methylbenzoate esters as the function of pKa of conjugate acid of leaving
group. The rate constants k2 for alkaline hydrolysis of these esters are also presented: cleavage of aryl
esters by HOOꢀ (filled squares); cleavage of alkyl esters by HOOꢀ (filled triangles); cleavage of aryl esters
by HOꢀ (open diamonds); cleavage of alkyl esters by HOꢀ (open down triangles).
Table 3
Slopes of the plots between the logarithm of rate constants (k1 or k2) and the pKa of conjugate acid of
leaving group for the aryl and alkyl esters of 4-nitro- and 4-methylbenzoate
Substituent in the acyl portion
log k1
log k2
Aryl
Alkyl
Aryl
Alkyl
Nitro
Methyl
)0.8 ꢂ 0.1
)0.8 ꢂ 0.3
)1.5 ꢂ 0.1
)2.3 ꢂ 0.3
)0.4 ꢂ 0.1
)0.1 ꢂ 0.3
)0.3 ꢂ 0.05
)0.2 ꢂ 0.7

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Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
The rate constants k2 for alkaline hydrolysis of these esters also provide two lines for
each of the aryl esters (the open squares) and the alkyl esters (the closed squares).
Both of these two lines are rather flat, compared with the lines for the HOOꢀ reac-
tions. For the cleavage of 4-methylbenzoate esters by HOOꢀ (Fig. 1B), the k1 values
are 101- to 102-fold smaller than those for 4-nitrobenzoate esters, as expected from
the electron-donating activity of its 4-methyl substituent. However, the relationship
between the k1 and the pKa is similar to that for the cleavages of 4-nitrobenzoate
esters, and the points for the aryl and the alkyl esters fit two different straight lines.
The line for the alkyl esters is far steeper than that for the aryl esters. The k2 values
also provide rather flat two lines. The slopes of all of these lines are similar to the
values for the 4-nitrobenzoate esters (Table 3).
3.2. Dependence of the magnitude of a-effect on substrate-structure in the nucleophilic
ester cleavage by HOOꢀ
The ratio of the rate constant k1 for the nucleophilic cleavage of an ester by
HOOꢀ to the corresponding value k2 for the cleavage by HOꢀ was taken as a mea-
sure of the a-effect of HOOꢀ. This ratio directly reflects the effect of leaving group on
the magnitude of a-effect. The difference in the electrophilicity of the carbonyl car-
bon atom of esters, due to either electron-donation or electron-withdrawal by the al-
cohol residue, is satisfactorily compensated in these k1=k2 ratios. In Fig. 2, these
ratios are plotted against the pKa of leaving group for both the 4-nitrobenzoate esters
and 4-methylbenzoate esters [12]. The open circles are for the cleavages of the aryl
esters of 4-nitrobenzoate, and the open squares are for the aryl 4-methylbenzoates.
For all of these aryl esters, the k1=k2 ratios are 102 or greater, confirming the substan-
tial a-effects of HOOꢀ. These results are consistent with the previous findings on the
cleavages of 4-nitrophenyl acetate and phenyl acetate [5,6].
The k1=k2 ratio gradually decreases with increasing pKa of leaving group. How-
ever, this change is modest (the slope ¼ )0.5). Note that the magnitude of a-effect
of HOOꢀ in these reactions should be still greater than the k1=k2 ratio, since HOOꢀ
having a smaller basicity is intrinsically less nucleophilic than is HOꢀ. The pKa of
HOOH (11.6) is by 4.1 U smaller than that of H2O (15.7), and thus the intrinsic nu-
cleophilicity of HOOꢀ (in the absence of a-effect) should be 102- to 103-fold smaller
than that of HOꢀ, as estimated from the Brønsted law [14]. Accordingly, the magni-
tude of a-effect in these reactions should be as large as 104- to 105-fold [15]. In the
cleavages of 2,2,2-trifluoroethyl esters of both 4-nitrobenzoate and 4-methybenzoate
(the closed circles and the closed squares numbered as (4) and (12), respectively, in
Fig. 2), the k1 is 14-fold greater than the k2. For these alkyl esters having a rather
good leaving group (pKa ¼ 12.4), the a-effect is also notable. This a-effect has
been further confirmed by the Brønsted plot in Fig. 3 for the nucleophilic cleavage
of 2,2,2-trifluoroethyl 4-nitrobenzoate by various nucleophiles. The point for
HOOꢀ notably deviates in positive direction from the straight line for ‘‘non-a-effect’’
nucleophiles (glycine, piperidine, and HOꢀ).
Quite significantly, in Fig. 2, the k1=k2 ratio for the cleavages of alkyl esters
drastically decreases as the leaving group becomes poorer (the closed circles for

Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
33
Fig. 2. Plots of k1/k2 ratios as the function of pKa of conjugate acid of leaving group for the cleavage of
aryl 4-nitrobenzoates (filled squares), alkyl 4-nitrobenzoates (filled triangles), aryl 4-methylbenzoates
(open diamonds), and alkyl 4-methylbenzoate esters (open down triangles).
Fig. 3. Plots of second-order rate constants at 30 ° C for nucleophilic cleavage of 2,2,2-trifluoroethyl
4-nitrobenzoate. Gly, glycine; SA, salicylaldoxime; Pip, piperidine; AHA, acetohydroxamic acid.
the 4-nitrobenzoates and the closed squares for the 4-methylbenzoates). The slope is
)1.1 and far steeper than the corresponding slope for the aryl esters. For the choline
esters (pKa of leaving group ¼ 13.2), the rate constants k1 for the HOOꢀ reactions
and k2 for the HOꢀ reactions are comparable with each other. With the 2-monoflu-
oroethyl ester (pKa ¼ 14.4) and the methyl ester (pKa ¼ 15.5), the k1 is even smaller
than the k2 by factors of 45 and 150, respectively. For these two substrates having

34
Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
very poor leaving groups, the a-effect is, if any, marginal. These arguments hold,
even when the difference in pKa between HOOH and H2O is taken into consider-
ation. Apparently, the a-effect in the nucleophilic cleavages by HOOꢀ is explicit only
when the substrates have good leaving groups.
It is noteworthy that the k1=k2 values for the cleavages of 4-nitrobenzoate esters
and 4-methylbenzoate esters fit the same line (for both the alkyl esters and the aryl
esters). The acyl portions of esters show no significant effects on the magnitude of the
present a-effects. Even when the electrophilicity of the carbonyl carbon atom is al-
tered by the electronic effects of acyl portion, this factor is satisfactorily normalized
in the k1=k2 ratios as described above.
3.3. a-Effects in the ester cleavages by various nucleophiles
The k2 values for the nucleophilic cleavage of 2,2,2-trifluoroethyl 4-nitrobenzoate
by salicylaldoxime and acetohydroxamic acid (pKa ¼ 9.2 and 9.4, respectively) are
0.01 and 0.7 sꢀ1 molꢀ1 dm3. As depicted in Fig. 3, these values notably deviate in po-
sitive direction from the straight line for ‘‘non-a-effect’’ nucleophiles. The a-effect is
evident here. However, the deviations for these two nucleophiles are rather small,
compared with that for HOOꢀ [16]. Thus, the rate constants for these two nucleo-
philes are 4.5 ꢃ 103- and 6.4 ꢃ 101-fold smaller than the corresponding k2 values
for alkaline hydrolysis, whereas the cleavage of the same ester by HOOꢀ is 14 times
as fast as alkaline hydrolysis. It is strongly indicated that ‘‘a-effect’’ nucleophiles hav-
ing smaller pKa require still better leaving group in the substrate in order to show
sufficient a-effect. These arguments are further supported by the fact that, in the
cleavage of 4-nitrophenyl acetate (having a very good leaving group), both salicyl-
aldoxime and acetohydroxamic acid are 5- to 10-fold more active than HOꢀ and
the a-effects are so remarkable [6]. This is in marked contrast with the results in
the cleavage of 2,2,2-trifluoroethyl 4-nitrobenzoate (vide ante). Predominant impor-
tance of leaving group for efficient a-effect has been further substantiated.
3.4. Origin of remarkable dependence of a-effect on substrate-structure
The essential role of leaving group in a-effect is associated with the difference in the
position of rate-determining transition-state in the course of the reaction-coordinate.
As was concretely evidenced by Jencks [1], Jencks and Fersht [17], Bender [2], Bruice
and Benkovic [3], and others (and also as indicated by the Hammond postulate) [18],
the position of transition-state gradually moves to the end of reaction coordinate as
the leaving group becomes poorer. When the leaving group is good, the transition-
state exists in the early stage of reaction (the solid line in Fig. 4A) and a bond between
the nucleophilic center and the carbonyl carbon atom is only partially formed
there. The rate of overall reaction is mostly governed by the efficiency of attack by
the nucleophile towards the substrate. Under these conditions, ‘‘a-effects’’ are
evident, since the transition-state is stabilized by: (i) the overlap of the non-bonding
electron pair of neighboring atom to the nucleophilic center and/or (ii) the orbital
hybridization among the carbonyl carbon atom, the nucleophile center atom, and

Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
35
Fig. 4. Transition-state diagram (A) for reaction with a tetrahedral intermediate and (B) for the reactions
with no intermediate. Good leaving group (solid line), poor leaving group (dashed line), rate-limiting tran-
sition-state (open circle).
the a-position atom bearing lone-pair electrons [1–4]. Consistently, the k1 value is not
much dependent on the pKa of leaving group in the cleavages of aryl esters of both 4-
nitrobenzoate (Fig. 1A) and 4-methylbenzoate (Fig. 1B). Furthermore, in Fig. 2, the
k1=k2 values for the alkyl esters having rather good leaving groups (e.g., the trifluoro-
ethyl esters (the number 4 and 12) and dichloroethyl esters (number 5 and 13)) almost

36
Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
fit the straight lines for the aryl esters. This result further confirms the critical role of
the basicity of leaving group in determining the magnitude of a-effect.
With the reactions involving a poor leaving group (the methyl esters and mono-
fluoroethyl esters), however, the removal of leaving group from the carbonyl carbon
atom is rate-limiting (the dashed line in Fig. 4A) and a tetrahedral intermediate is
formed in pre-equilibrium. The reaction rate is mostly governed by the basicity of
leaving group, and the plot of log k1 vs. pKa is accordingly steep (the closed circles
in Figs. 1A and B). Under these conditions, the pre-equilibrium concentration of
the tetrahedral intermediate is little affected by the ‘‘a-effects’’ in nucleophiles. Even
though the pre-equilibrium formation of this intermediate is accelerated by the lone-
pair electrons in the a-position, the backward reaction is also accelerated in the same
magnitude. Consistently, the rate constants for the cleavages of methyl esters and
monofluoroethyl esters by HOꢀ (k2) are even larger than those by HOOꢀ (k1), re-
flecting directly the difference in intrinsic nucleophilicity between HOꢀ and HOOꢀ.
The substituent in the acyl portion of substrate (benzoates in this study) alters the
electrophilicity of the carbonyl carbon and thus affects the nucleophilic attack by
HOOꢀ and HOꢀ (and other nucleophiles) in a similar extent to each other. As the
result, the magnitude of a-effect is almost independent of the structure of acyl group.
We have argued above the origin of a-effects simply in terms of a stepwise reaction.
However, there is also a possibility that the reactions are concerted ones without very
stable tetrahedral intermediates. It is not very clear at present, which is really the case.
However, the arguments on the origin of a-effects are unchanged in either of the cases.
Acknowledgments
This study was partially supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sport, Culture and Technology, Japan.
References
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111 and references cited therein.
[2] (a) M.L. Bender, Mechanisms of Homogeneous Catalysis from Protons to Proteins, Wiley-
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Wiley-Interscience, New York, 1984.
[3] T.C. Bruice, S.J. Benkovic, in: Bioorganic Mechanisms, vol. 1, W.A. Benjamin, Inc, New York, 1966.
[4] J.O. Edwards, R.G. Pearson, J. Am. Chem. Soc. 84 (1962) 16–24.
[5] W.P. Jencks, J. Carriuolo, J. Am. Chem. Soc. 82 (1960) 1778–1786.
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[7] L. Stryer, Biochemistry, W.H. Freeman and Company, New York, 1988.
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[11] A. Marquet, J. Jacques, Org. Synth. Coll. VI (1988) 175.
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[12] (a) The pKa values used in this paper were taken from M.G. Evans, N. Uri, J. Chem. Soc. Faraday
Trans. 45 (1949) 224–230 (for hydrogen peroxide);
(b) E.P. Serjeant, B. Dempsey, IUPAC Chemical Data Series, 23, 1979 (2,2,2-trifluoroethanol,
2,2-dichloroethanol, and methanol);
(c) Kirk-Othmer Encyclopedia of Chemical Technology, fourth ed., Wiley-Interscience, New York,
11 (1994) 521 (2-fluoroethanol);
(d) J.T. Edsell, J. Wyman, Biophysical Chemistry, Academic Press Inc, New York, 1958 (glycine);
(e) H.K. Hall Jr., J. Am. Chem. Soc. 79 (1957) 5441–5444 (piperidine);
(f) A.L. Green, B. Saville, J. Chem. Soc. (1956) 3887–3892 (salicylaldoxime);
(g) W.M. Wise, W.W. Breandt, J. Am. Chem. Soc. 77 (1955) 1058–1059 (acetohydroxamic acid);
(h) P.J. Pearce, R.J.J. Simkins, Can. J. Chem. 46 (1968) 241–248 (4-methylphenol);
(i) R.L. Hinman, J. Org. Chem. 23 (1958) 1587–1588 (hydrazine). The pKa of choline was evaluated
by using Hammett relationship in D.D. Perrin, B. Dempsey, E.P. Serjeant, pKa Prediction for
Organic Acids and Bases, Chapman and Hall, London, 1981. The pKa values for all other
nucleophiles are from Kagaku Binran II-317, ed. by Chemical Society of Japan, Maruzen, Japan,
1993.
[13] For the nucleophilic cleavages of aryl esters, there should exist small amounts of peracids in the
mixtures. However, they were rapidly cleaved and not detected by the HPLC. In this study, the rate
constants were determined by using the amount of ester left unchanged in the mixtures. Thus this
factor causes no effect on the present kinetic studies.
[14] When the slopes in the plot of log k1 vs. pKa are 0.5 and 0.7, respectively, the correction factors
should be 1.1 ꢃ 102 and 7.4 ꢃ 102. The slope of this plot for the cleavage of 4-nitrophenyl acetate is
0.68 [5], and the plot in Fig. 3 in text gave a similar value.
[15] Still more precise evaluation of the magnitudes of a-effects was quite difficult, since steric hindrance
was not negligible in nucleophilic reactions and this factor also induced some deviation in the
Brønsted plots (see [2]).
[16] The cleavage of 2,2,2-trifluoroethyl 4-nitrobenzoate by hydrazine as ‘‘a-effect’’ nucleophile
(pKa ¼ 8.1) was also examined. However, it was too poorly active, compared with the cleavages by
water, to measure the catalytic constant precisely. It was concluded that this nucleophile having small
pKa value exhibits no significant a-effect.
[17] W.P. Jencks, A.R. Fersht, J. Am. Chem. Soc. 92 (1970) 5442–5452.
[18] G.S.J. Hammond, J. Am. Chem. Soc. 77 (1955) 333–334.