Kinetic study on aminolysis of aryl X-substituted-cinnamates in acetonitrile: Differential medium effect determines reactivity and reaction mechanism

Article abstract of DOI:10.1139/cjc-2018-0310

A kinetic study on nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f) and Y-substituted-phenyl cinnamates (2a-2g) with a series of alicyclic secondary amines in MeCN at 25.0 ± 0.1 °C is reported. The Br?nsted-type pl

Full text of DOI:10.1139/cjc-2018-0310

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Kinetic Study on Aminolysis of Aryl X-Substituted-Cinnamates in Acetonitrile: Differential
Medium Effect Determines Reactivity and Reaction Mechanism1
Ik-Hwan Um,*a Ae-Ri Baea and Julian M. Dust*b
aDepartment of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Korea
E-mail: ihum@ewha.ac.kr
bDepartments of Chemistry and Environmental Science, Grenfell Campus-Memorial University of
Newfoundland, Corner Brook, Newfoundland and Labrador A2H 5G4, Canada
E-mail: jmdust@grenfell.mun.ca
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1This article is dedicated to Prof. Emeritus Erwin Buncel, Queen’s University, our teacher and mentor in
the exploration of physical organic chemistry.
Abstract
A kinetic study on nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted-cinnamates
(1a-1f) and Y-substituted-phenyl cinnamates (2a-2g) with a series of alicyclic secondary amines in
MeCN at 25.0 ± 0.1 oC is reported. The Brønsted-type plots for the reactions of 1a-1f are linear with βnuc
= 0.47 ~ 0.50, indicating that the bond formation between the amine nucleophile and the electrophilic
center is advanced slightly in the transition state (TS). The Brønsted-type plot for the reactions of 2a-2g
with piperidine is also linear with βlg = ‒0.66, a typical βlg value for reactions reported previously to
proceed through a concerted mechanism. Furthermore, the Hammett plot correlated with σ– constants
results in much better linearity than that correlated with σo constants, implying that expulsion of the
leaving-group is advanced in the rate-determining step (RDS). Thus, the reactions are concluded to
proceed through a concerted mechanism. The Hammett plots for the reactions of 1a-f consist of two
intersecting straight lines, while the corresponding Yukawa-Tsuno plots exhibit excellent linear
correlations with ρX = 0.62 ~ 0.71 and r = 0.65 ~ 0.68. Apparently, the nonlinear Hammett plots are not
due to a change in the reaction mechanism (or the RDS) but are caused by stabilization of the substrate
possessing an electron-donating group (EDG) in the cinnamoyl moiety through resonance interactions
between the EDG and the C=O bond of the substrate. Medium effects on reactivity and reaction
mechanism are also discussed.
Keywords: Aminolysis, Brønsted-type plot, Yukawa-Tsuno plot, Concerted mechanism, Differential
medium effect
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Introduction
Aminolysis of esters has been reported to proceed either through a concerted mechanism or via a
stepwise pathway with one or two intermediates (i.e., a zwitterionic tetrahedral intermediate T± and its
deprotonated form T‒) as shown in Scheme 1.1-10 Factors suggested to affect the reaction mechanism
include: nature of the electrophilic center (P=O, P=S, C=O and C=S), basicity of the leaving group and
the incoming amine, electronic nature of the substituent in the nonleaving group, type of reaction
medium (protic vs. aprotic solvents), etc.1-10
We have reported that aminolyses of 2,4-dinitrophenyl diphenylphosphinate (a P=O centered
electrophile) and O-2,4-dinitrophenyl diphenylphosphinothioate (a P=S centered electrophile) proceed
through a concerted mechanism on the basis of a linear Brønsted-type plot with βnuc = 0.5 ± 0.1.5 In
contrast, aminolyses of 2,4-dinitrophenyl benzoate and 2,4-dinitrophenyl phenyl carbonate (C=O
centered electrophiles) have been suggested to proceed via a stepwise mechanism with a change in the
rate-determining step (RDS) as the incoming amine becomes more basic than the leaving group by 4 ~ 5
pKa units,6,7 while the corresponding reactions of O-2,4-dinitrophenyl thionobenzoate and O-2,4-
dinitrophenyl phenyl thionocarbonate (C=S centered electrophiles) proceed through a stepwise
mechanism, in which breakdown of T± to the products occurs via catalytic and uncatalytic routes
competitively.7,8
The nature of the reaction medium (e.g., protic or aprotic solvent) has also been reported to govern the
reaction mechanism. We have found that aminolyses of aryl benzoates and aryl phenyl carbonates
proceed through a stepwise mechanism both in H2O and in MeCN.6,7 However, the reactions in the
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aqueous medium proceed through the uncatalytic route only, while those in MeCN proceed via the
catalytic and uncatalytic routes competitively.6,7 Importantly, the catalytic path involves a 6-membered
cyclic transition state (TS) in which a proton is efficiently transferred from amine to the leaving group.6,7
A key question arises: Is this catalytic path general for similar aminolyses of esters in MeCN?
It is now firmly understood that the basicity of the leaving group and incoming amine determines the
RDS for reactions which proceed through a stepwise mechanism, i.e., a change in the RDS for a
stepwise reaction occurs from breakdown of T± to its formation as the incoming amine becomes more
basic than the leaving group (or the leaving group becomes less basic than the amine nucleophile) by 4 –
5 pKa units.2-7 However, the effect of any nonleaving-group substituent on the RDS is not so clearly
understood. Gresser and Jencks have concluded that the RDS for the reactions of diaryl carbonates with
quinuclidines is dependent on the electronic nature of the substituent in the nonleaving group of the
substrate.2c A similar conclusion has been drawn by Castro et al. for pyridinolysis of 2,4-dinitrophenyl
X-substituted-benzoates and S-2,4-dinitrophenyl X-substituted-thiobenzoates.9 On the contrary, we have
shown that the electronic nature of the substituent X in the nonleaving group does not affect the RDS for
aminolysis of various esters, e.g., 2,4-dinitrophenyl X-substituted-benzoates,5a O-4-nitrophenyl X-
substituted-thionobenzoates,8 and 2,4-dinitrophenyl X-substituted-benzenesulfonates.10
We have now carried out a systematic study on nucleophilic substitution reactions of 2,4-
dinitrophenyl X-substituted-cinnamates (1a-1f) and Y-substituted-phenyl cinnamates (2a-2g) with a
series of alicyclic secondary amines in MeCN (Scheme 2). We have introduced not only a series of
structurally similar amines, whose pKa values are known in MeCN, but also various substituents X and
Y in the cinnamoyl moiety and the leaving aryloxide, respectively, to investigate the reaction
mechanism thoroughly. Medium effects on the reactivity and reaction mechanism have also been
discussed by comparing the current kinetic data with those reported previously for the corresponding
reactions performed in H2O.11 The current study probes the generality of the stepwise mechanism in
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MeCN where catalysis via the 6-membered cyclic TS dominates.
Experimental
Materials. Compounds 1a-1f and 2a-2g were readily prepared from the reaction of X-substituted-
cinnamoyl chloride with the relevant Y-substituted-phenol under presence of triethylamine in anhydrous
1
ether as reported previously.11,12 Their purity was checked by means of melting point and H NMR
spectrum. MeCN was dried and purified by distillation over phosphorus pentoxide under nitrogen.
Amines and other chemicals were of the highest quality commercially available and used as purchased.
Kinetics. The kinetic study was performed using a UV-vis spectrophotometer for slow reactions (t1/2 ≥
10 s) or a stopped-flow spectrophotometer for fast reactions (t1/2 < 10 s) equipped with a constant
temperature circulating bath to maintain the reaction temperature at 25.0 ± 0.1°C. All reactions were
carried out under pseudo-first-order conditions in which the amine concentration was a minimum of 20
times greater than the substrate concentration. Solutions were transferred using gas-tight syringes under
nitrogen. The reactions were followed by monitoring the leaving aryloxide (or its conjugate acid) at a
fixed wavelength corresponding to the maximum absorption of Y-C6H4O– (λmax). Other details in
experimental methods were similar to the ones described previously.5,6
Product Analysis. Y-Substituted-phenoxide (Y-C6H4O– and/or its conjugate acid Y-C6H4OH) was
liberated quantitatively and identified as one of the reaction products by comparison of the UV-vis
spectra after completion of the reactions with those of the authentic samples under the same kinetic
conditions.
Results
All reactions in this study obeyed first-order kinetics. Pseudo-first-order rate constants (kobsd) were
determined from the equation ln (A∞ – At) = –kobsdt + C via plots of ln (A∞ – At) versus time t. The plots
of kobsd vs. amine concentration were linear passing through the origin, indicating that general base
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catalysis by a second amine molecule is absent in this study. Thus, the second-order rate constants (kN)
were calculated from the slope of linear plots of kobsd vs. amine concentration. It is estimated from at
least three replicate runs that the uncertainty in rate constants is less than ± 3 %. The kN values
determined in this way are listed in Tables 1 – 3.
Discussion
Effect of Amine Basicity on Reactivity and Mechanism. As shown in Table 1, the second-order
rate constant for the reactions of 2,4-dinitrophenyl X-substituted-cinnamates (X = 4-NO2, H and 4-MeO)
decreases as the amine basicity decreases except for the reaction with piperazine which possesses two
basic sites (e.g., kN for the reaction of 1a decreases from 929 to 217 and 77.9 M–1s–1 as the pKa for the
conjugate acid of the amine decreases from 18.8 to 17.6 and 16.6, in turn). A similar result is shown for
the corresponding reactions of 1c and 1e, although the reactivity of these substrates decreases as the
substituent X in the cinnamoyl moiety changes from a strong electron-withdrawing group (EWG) to an
electron-donating group (EDG).
The effect of amine basicity on reactivity is illustrated in Figure 1. The Brønsted-type plots exhibit
excellent linear correlations (R2 > 0.99) with βnuc = 0.47 ~ 0.50 when kN and pKa values are statistically
corrected using p and q (i.e., p = 2 and q = 1 except q = 2 for the reaction with piperazine).14 Such small
βnuc values found in this study imply that bond formation between the amine nucleophile and the
electrophilic center is advanced only a little in the TS. Two possibilities arise for the current reactions,
i.e., either the reactions proceed through a concerted mechanism with a TS structure similar to TS1 or via
a stepwise pathway with TS2 (Chart 1), where expulsion of the leaving group is not advanced.
Linear Brønsted-type plots with βnuc = 0.5 ± 0.1 have often been reported for reactions that proceed
through a concerted mechanism, e.g., aminolyses of 2,4-dinitrophenyl diphenylphosphinate, O-2,4-
dinitrophenyl diphenylphosphinothioate5 and S-2,4-dinitrophenyl thiobenzoate.9a Therefore, literature
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comparison suggests that the current reactions proceed also through a concerted mechanism.
However, one cannot exclude the possibility that the current reactions proceed through a stepwise
mechanism with TS2, because the βnuc value found in this study is larger only slightly than an upper limit
of βnuc for reactions proceeding through a stepwise mechanism with formation of T± being the RDS (e.g.,
βnuc = 0.36 ± 0.18 for aminolysis of aryl benzoates).6a Thus, the linear Brønsted-type plots shown in
Figure 1 alone are insufficient to conclude whether the reactions proceed through a concerted
mechanism with a TS structure similar to TS1 or via a stepwise pathway involving TS2. The key is that
for the TS2 path expulsion of the leaving group cannot be advanced.
Effect of Leaving-Group Basicity on Reactivity and Mechanism. To examine whether expulsion
of the leaving group is advanced in the RDS or not, reactions of Y-substituted-phenyl cinnamates (2a-2g)
with piperidine have been carried out. As shown in Table 2, the second-order rate constant, kN, decreases
as the basicity of the leaving aryloxide increases, e.g., kN decreases from 90.3 to 3.93 × 10–2 and 1.11 ×
10–3 M–1s–1 as the pKa of the conjugate acid of the leaving group increases from18.7 to 23.1 and 25.3, in
turn (Table 2).
The effect of leaving-group basicity on the reactivity of 2a-2g is shown graphically in Figure 2. The
Brønsted-type plot exhibits an excellent linear correlation with βlg = –0.66. Such a good linear plot (R2 =
0.996) implies that the reactions proceed without changing the reaction mechanism (or the RDS), even
though the basicity of the leaving group varies ca. 7 pKa units.
A curved Brønsted-type plot has often been reported for aminolysis of esters, which proceeds through
a stepwise mechanism with a change in the RDS, e.g., βlg changes from –(1.5 ± 0.3) to –(0.3 ± 0.1) as
the RDS changes from breakdown of T± to its formation.2-6 Clearly, the βlg value found in this study (i.e.,
βlg = –0.66) is too large for reactions proceeding through a stepwise mechanism with formation of T±
being the RDS. Furthermore, a βlg value of –(0.6 ± 0.1) is typical for reactions reported previously to
proceed through a concerted mechanism, e.g., aminolysis of aryl diphenylphosphinates and O-aryl
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diphenylphosphinothioates.5 Thus, one can also conclude that the current reactions proceed through a
concerted mechanism with a TS structure similar to TS1 but not via a stepwise pathway with TS2.
To obtain more confirmative information on the TS structure, Hammett plots have been constructed
using σ– and σo constants. It is noted that the major difference between TS1 and TS2 is the position of the
partial negative charge. In TS1, a partial negative charge develops on the O atom of the leaving
aryloxide, which can be delocalized on the substituent Y in the leaving group through resonance
interaction. In contrast, in TS2, a negative charge develops partially on the O atom of the carbonyl group
but not on the leaving group, as a result of the fact that leaving-group expulsion is not advanced in TS2.
Accordingly, if expulsion of the leaving group occurs in the RDS (i.e., TS1), use of σ– constants
should result in a better Hammett correlation than using σo constants. On the contrary, if expulsion of
the leaving group is not advanced in the RDS (i.e., TS2), σo constants should exhibit a better correlation
with log kN than σ– constants. In fact, Figures 3A and B show that the Hammett plot correlated with σ–
constants results in a much better correlation (A, ρY = 2.89 and R2 = 0.990) than that obtained with σo
constants (B, ρY = 3.67 and R2 = 0.916). This indicates clearly that expulsion of the leaving group occurs
in the TS and that the reactions proceed through a concerted mechanism with TS1.
Effect of Nonleaving-Group Substituent X on Reactivity and Reaction Mechanism. Our study
has further extended to the reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f) with
piperidine, piperazine and morpholine nucleophiles to investigate effects of the electronic nature of
substituent X on reactivity and reaction mechanism. As shown in Table 3, the reactivity of 1a-1f
decreases as the substituent X in the cinnamoyl moiety changes from a strong EWG to a strong EDG,
e.g., the kN value for the reactions with piperidine decreases from 929 to 249 and 78.0 M–1s–1 as X
changes from 4-NO2 to H and 4-OH, respectively. Similar results are shown for the reactions with
piperazine and morpholine, although the less basic piperazine exhibits larger kN values than the more
basic piperidine. However, this is not unusual given that piperazine possesses two nucleophilic sites.
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The effect of substituent X on reactivity is illustrated in Figure 4. It is noted that each Hammett plot
consists of two intersecting straight lines, i.e., the ρX value for the reactions with piperidine increases
from 0.75 to 1.38 as the substituent X changes from EWGs to EDGs. Comparable results are shown for
the corresponding reactions with piperazine and morpholine. Since nonlinear or biphasic Hammett plots
have often been taken as evidence for a change in RDS,17 one might suggest that the current aminolysis
proceeds also through a stepwise mechanism with a change in RDS, e.g., from rate-determining
formation of T± to its breakdown as the substituent X changes from EDGs to EWGs.
The above argument appears to be reasonable since the rate of nucleophilic attack (the k1 process in
Scheme 1) would be accelerated by an EWG in the cinnamoyl moiety but retarded by an EDG. Thus, a
large ρX value would be expected when formation of T± is the RDS. In contrast, an EWG in the
cinnamoyl moiety would inhibit expulsion of the leaving group from T± (the k2 process in Scheme 1),
because the leaving aryloxide departs from T± with its bonding electron pair. Therefore, it is plausible to
expect a small ρX value when breakdown of T± to the products is the RDS due to the opposite substituent
effects. In fact, Jencks found that the ρX value for reactions of X-substituted benzaldehydes with
semicarbazide in weakly acidic medium (e.g., pH = 3.9) decreases from 0.91 to nearly zero as the
substituent X changes from EDGs to EWGs, and attributed the nonlinear Hammett plot to a change in
the RDS.17a
However, we propose that the nonlinear Hammett plots shown in Figure 4 are not due to a change in
the RDS. In fact, the current kinetic results discussed above support the idea that the reactions proceed
through a concerted mechanism. We, thus, propose that the nonlinear Hammett plots are due to
stabilization of the substrate in the ground state (GS) through resonance interactions as illustrated by
resonance structures I and II (Chart 2). This idea is consistent with the fact that the substrates possessing
an EDG in the cinnamoyl moiety exhibit negative deviation from the linear line composed of substrates
1a-c and such deviation is more significant for the substrate bearing a stronger EDG (e.g., 1f).
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To verify the above argument, Yukawa-Tsuno plots have been constructed in Figure 5. It is noted that
the r value in the Yukawa-Tsuno equation (1) represents the resonance demand of the reaction center or
the extent of the resonance contribution, while the term (σ+ – σo) stands for the resonance substituent
constant that measures the capacity for π-delocalization of a given π-electron donor substituent.18,19
log (kX /kH) = ρX [σo + r(σ+ – σo)]
(1)
As shown in Figure 5, the Yukawa-Tsuno plots exhibit excellent linear correlations (R2 > 0.995) with
ρX = 0.62 ~ 0.71 and r = 0.66 ± 0.02. Such linear Yukawa-Tsuno plots indicate that the nonlinear
Hammett plots in Figure 4 are clearly not due to a change in the RDS. Thus, one can conclude that the
electronic nature of the substitutent X in the cinnamoyl moiety does not influence the reaction
mechanism including the RDS, although it affects the reactivity of the substrates. Furthermore, the
current study has clearly shown that deduction of reaction mechanism based solely on a linear or
nonlinear Hammett plot may be misleading.
Differential Medium Effects on Zwitterionic Intermediate T± vs. Concerted Transition State TS1.
As discussed above, aminolysis of 1a-1f and 2a-2g in MeCN proceeds through a concerted mechanism
with a TS structure similar to TS1. This is the same mechanism reported previously for the
corresponding reaction carried out in H2O,11 indicating that the nature of the reaction medium (e.g.,
protic vs. aprotic) does not affect the reaction mechanism for the aminolysis of 1a-1f and 2a-2g.
However, Tables 1 ~ 3 show that the amines used in this study are more reactive in MeCN than in H2O.
This is an unexpected result based on the Hughes-Ingold rule.20 According to the rule, rates of
nucleophilic substitution reactions between neutral reactants are expected, and have been found, to
decrease upon changing the reaction medium from a protic solvent to an aprotic one.21,22 In fact, our
previous studies on aminolyses of various esters (e.g., phenyl Y-substituted-phenyl carbonates,7 O-4-
nitrophenyl X-substituted-thionobenzoates8b and 4-pyridyl X-substituted-benzoates23), which proceed
through a stepwise mechanism with T± as an intermediate, have shown that the amines become less
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reactive up to 400 times upon changing the medium from H2O to MeCN.
It is clear that medium effects on the stability of T± and TS1 would be different. The negative charge
on the O atom of T± could be stabilized through strong H-bonding interactions in H2O but would be
highly destabilized in MeCN due to the electronic repulsion between the negatively charged O atom of
T± and the negative dipole end of MeCN.21,22 This idea is consistent with the report that amines become
less reactive in MeCN for the reactions proceeding through T±,7,8b,23 although the amines are 6 ~ 8 pKa
units more basic in this aprotic solvent.13 In contrast, one might expect that the difference in stability of
TS1 in the two solvents is not significant. In this regard, in TS1 charge is delocalized and, therefore, TS1
would be neither strongly stabilized through H-bonding interactions in H2O nor highly destabilized by
electronic repulsion in MeCN. This accounts for the kinetic results that the amines are more reactive in
MeCN, where amines are more basic by 6 ~ 8 pKa units, than in water even though the reactions proceed
through the same mechanism (i.e., a concerted mechanism) in both solvents.
We have recently shown that aminolyses of various esters (e.g., 4-nitrophenyl 3,5-dinitrobenzoate, 4-
pyridyl X-substituted-benzoates, phenyl Y-substituted-phenyl carbonates, etc.) in MeCN proceed
through a stepwise mechanism with T±, which decomposes to reaction products through catalytic and
uncatalytic routes competitively.7,8b,23 The catalytic route proceeds through a 6-membered cyclic TS
(e.g., TS3 in Chart 3) to gain stability via intramolecular H-bonding interactions. Note that the second
amine molecule in TS3 relays a proton from the aminium moiety of T± to the leaving aryloxide. It is
apparent that such proton transfer could also increase nucleofugality of the anionic leaving-group in the
aprotic solvent (MeCN). On the contrary, protonation of the leaving group by a second amine molecule
is not necessary for the reactions carried out in the aqueous medium, because the anionic nucleofuge
(e.g., ArO‒) could be stabilized through H-bonding with H2O. This idea is consistent with the report that
decomposition of T± to products occurs through catalytic and uncatalytic routes competitively in MeCN
but the catalytic route is often absent in H2O.7,8b,23 Thus, we propose that differential medium effects on
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T± and TS1 are responsible for the contrasting reactivity and reaction mechanism observed for the
reactions in MeCN and in H2O.
Conclusion
We have concluded that the current reactions of 1a-1f and 2a-2g proceed through a concerted
mechanism with a TS structure similar to TS1 and that nature of the reaction medium (e.g., protic versus
aprotic) and substituents X and Y affects reaction rates but does not influence the reaction mechanism
on the basis of the following kinetic results:
(1) The Brønsted-type plots for the reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f)
are linear with βnuc = 0.47 ~ 0.50, indicating that bond formation between the nucleophilic amine and the
electrophilic center is advanced only a little in the TS.
(2) The Brønsted-type plot for the reactions of Y-substituted-phenyl cinnamates (2a-2g) with
piperidine is linear with βlg = ‒0.66, a typical βlg value for reactions proceeding through a concerted
mechanism.5-9
(3) The use of σ– constants result in a better Hammett correlation than σo constants for the reactions of
2a-2g with piperidine, indicating that expulsion of the leaving group is advanced in the RDS.
(4) The Hammett plots for the reactions of 1a-f with piperidine, piperazine and morpholine are
nonlinear while the corresponding Yukawa-Tsuno plots exhibit excellent linear correlations with
significant r, resonance interaction values. This indicates that the nonlinear Hammett plots are not due to
a change in RDS in a stepwise mechanism but are caused by stabilization of the substrates possessing an
EDG in the cinnamoyl moiety through resonance interactions.
(5) The amines used in this study are more reactive in MeCN than in H2O, implying that
destabilization of TS1 in the aprotic solvent is not significant and that the enhanced amine basicity is
responsible for their increased reactivity in the aprotic solvent. In other words, this result highlights a
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differential solvent effect in these systems.
Acknowledgements. This research was supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015-R1D1A1A-
01059624). Acknowledgement is also extended to Grenfell Campus-Memorial University (Vice-
President’s Research Fund) (J. M. D.).
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15. Jencks, W. P.; Regenstein, J. In Handbook of Biochemistry, 2nd ed.; Sober, H. A., Ed.; Chemical
Rubber Publishing Co.; Cleveland, OH, 1970; p J-195.
16. Trummal, A.; Rummel, A.; Lippmaa, E.; Burk, P.; Koppel, I. A. J. Phys. Org. Chem. 2009, 113,
6206.
17. (a) Jencks, W. P. Catalysis in Chemistry and Enzymology, McGraw-Hill; New York, 1969; p 480. (b)
Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper Collins
Publishers: New York, 1987; Chapter 8.
14

Page 15 of 23
18. (a) Tsuno, Y.; Fujio, M. Adv. Phys. Org. Chem. 1999, 32, 267. (b) Tsuno, Y.; Fujio, M. Chem. Soc.
Rev. 1996, 25, 129 – 139. (c) Yukawa, Y.; Tsuno, Bull. Y. Chem. Soc. Jpn. 1959, 32, 965.
19. (a) Mishima, M.; Abboud, J-L. M. J. Phys. Org. Chem. 2016, 29, 77. (b) Badal, M. M. R.; Zhang,
M.; Kobayashi, S.; Mishima, M. Bull. Chem. Soc. Jpn. 2013, 86, 856. (c) Badal, M. M. R. ; Zhang, M.;
Kobayashi, S.; Mishima, M. J. Phys. Org. Chem. 2013, 26, 1071. (d) Fujio, M.; Umezaki, Y.; Alam,
M. A.; Kikukawa, K.; Fujiyama, R.; Tsuno, Y. Bull. Chem. Soc. Jpn. 2006, 79, 1091.
20. Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1935, 244.
21. C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 2nd ed.; VCH Publishers,
Cambridge, 1988, p 69.
22. (a) Buncel, E.; Stairs, R. A. Solvent Effects in Chemistry, 2nd ed.; Wiley, New York, 2016. (b)
Buncel, E.; Stairs, R.; Wilson, H. The Role of the Solvent in Chemical Reactions; Oxford University
Press, Oxford, 2003.
23. Um, I. H.; Bae, A. R. J. Org. Chem. 2012, 77, 5781.
15

Page 16 of 23
Caption
Scheme 1. Reaction pathways for aminolysis of esters.
Scheme 2. Aminolysis of Y-substituted-phenyl X-substituted-cinnamates (1a-1f and 2a-2g).
Chart 1. Two possible transition state structures.
Chart 2. Resonance structures that stabilize the GS of the substrate.
Chart 3. 6-Membered cyclic TS proposed previously for aminolysis of aryl benzoates in MeCN.
Figure 1. Brønsted-type plots for aminolysis of 2,4-dinitrophenyl X-substituted-cinnamates in MeCN at
25.0 ± 0.1 oC. X = 4-NO2 (1a, ▲); X = H (1c, ○); X = 4-MeO (1e, ●). The identity of points is given in
Table 1.
Figure 2. Brønsted-type plot for the reactions of Y-substituted-phenyl cinnamates (2a-2g) with
piperidine in MeCN at 25.0 ± 0.1 oC. The identity of points is given in Table 2.
Figure 3. Hammett plots correlated with σ– (A) and σo constants (B) for the reactions of Y-substituted-
phenyl cinnamates (2a-2g) with piperidine in MeCN at 25.0 ± 0.1 oC. The identity of points is given in
Table 2.
Figure 4. Hammett plots for reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f) with
o
piperidine (●), piperazine (□) and morpholine (○) in MeCN at 25.0 ± 0.1 C. The identity of points is
given in Table 3.
Figure 5. Yukawa-Tsuno plots for reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f) with
o
piperidine (●), piperazine (□), and morpholine (○) in MeCN at 25.0 ± 0.1 C. The identity of points is
given in Table 3.
16

Page 17 of 23
Tables 1 ~ 3 for cjc-2018-0310
Table 1. Summary of Second-Order Rate Constants (kN) for Aminolysis of 2,4-Dinitrophenyl X-
Substituted-cinnamates (1a, 1c and 1e) in MeCN at 25.0 ± 0.1 oC.
kN / M–1s–1
amine
pKaa 1a (X = 4-NO2)
1c (X = H)
1e (X = 4-MeO)
109 ± 3 (92.5)b
102 ± 3 (83.8)b
114 ± 4 (50.7)b
1 piperidine
2 3-methylpiperidine
3 piperazine
18.8
18.6
929 ± 19 (640)b
758 ± 17 (621)b
249 ± 5 (193)b
218 ± 5 (186)b
258 ± 7 (115)b
18.5 1020 ± 30 (264)b
4 1-(2-hydroxyethyl)
piperazine
17.6 217 ± 6
63.0 ± 1.3
27.3 ± 0.8
5 morpholine
16.6 77.9 ± 2.1 (65.0)b 24.4 ± 0.5 (22.7)b 11.0 ± 0.2 (10.6)b
aThe pKa data in MeCN were taken from ref. 13. bThe kN values in the parenthesis were taken
from ref. 11 for the corresponding reaction in H2O.
Table 2. Summary of the Second-Order Rate Constants (kN) for Reactions of Y-Substituted-
phenyl Cinnamates (2a-2g) with Piperidine in MeCN at 25.0 ± 0.1 oC.
entry
2a
Y
pKa (Y-C6H4OH)
18.7a
102 kN / M–1s–1
9030 ± 185 (156)c
166 ± 4 (12.3)c
3,4-(NO2)2
4-NO2
2b
2c
20.9a
4-CHO
4-COMe
4-CO2Et
3-COCH3
4-Cl
22.4b
19.2 ± 0.6 (4.03)c
3.93 ± 0.11 (1.71)c
2.62 ± 0.05 (1.24)c
0.124 ± 0.003 (0.160)c
0.111 ± 0.003
2d
2e
23.1b
23.8b
2f
25.0b
2g
25.3b
aThe pKa values of Y-substituted phenols in MeCN were taken from ref. 15. bThe pKa values

Page 18 of 23
were calculated from the equation, pKa (in MeCN) = 1.65 pKa (in H2O) + 9.8, which was derived
from the pKa data in refs. 15 and 16. cThe kN values in the parenthesis were taken from ref. 11 for
the corresponding reaction in H2O.
Table 3. Summary of Second-Order Rate Constants for Aminolysis of 2,4-Dinitrophenyl X-
Substituted-Cinnamates (1a-1f) in MeCN at 25.0 ± 0.1 oC.
kN / M–1s–1
entry
1a
1b
1c
1d
1e
1f
X
4-NO2
4-Cl
piperidine
929 ± 26 (640)a
337 ± 8 (253)a
249 ± 5 (193)a
165 ± 5 (140)a
109 ± 3 (92.5)a
78.0 ± 2.3
piperazine
1020 ± 30
360 ± 10
258 ± 7
193 ± 6
114 ± 4
morpholine
77.9 ± 2.3 (65.0)a
30.9 ± 0.6 (27.0)a
24.4 ± 0.7 (22.7)a
16.8 ± 0.3 (15.8)a
11.0 ± 0.2 (10.6)a
9.34 ± 0.19
H
4-Me
4-MeO
4-OH
90.2 ± 2.1
aThe kN values in the parenthesis were taken from ref. 11 for the corresponding reaction in
H2O.

Page 19 of 23
Schemes 1 and 2 for cjc-2018-0310
kc
O
O
O
k1
H
k2
HN
R C O Ar
R C
O Ar
N
R C O Ar
NH
k-1
PH
T
k3[NH]
H
O
O
O Ar
R C O Ar
N
R C N
P
T
Scheme 1. Reaction pathways for aminolysis of esters
O
O
C
H
N
kN
CH CH C
O
CH CH
O
HN
Y
Y
X
X
1a-f or 2a-g
NO2
O
O
CH CH C
O
NO2
CH CH C O
Y
X
1
2
X = 4-NO2 (1a), 4-Cl (1b), H (1c), 4-Me (1d),
4-MeO (1e), 4-OH (1f).
Y = 3,4-(NO2)2 (2a), 4-NO2 (2b), 4-CHO (2c),
4-COMe (2d), 4-COOEt (2e), 3-COMe (2f),
4-Cl (2g).
R
: R = H or Me; Z = CH , NH, NCH CH OH, O.
Z
HN
=
HN
2
2
2
Scheme 2. Aminolysis of Y-substituted-phenyl X-substituted-cinnamates (1a-1f and 2a-2g).

Page 20 of 23
Charts 1 ~ 3 for cjc-2081-0310

O
C
O

O
Ph
O
CH CH
C
Ph CH CH

Y
Y

NH
NH
TS2
TS1
Chart 1. Two possible transition state structures.
O
O
HO
CH CH C OAr
HO
CH CH C OAr
I
II
Chart 2. Resonance structures that stabilize the GS of the substrate.

Ar'
O
O
Ar
C
N
H
N

H
TS3
Chart 3. 6-Membered cyclic TS proposed previously for aminolysis of aryl benzoates in
MeCN.

Page 21 of 23
Figures 1 ~ 5 for cjc-2018-0310
4
1
2
3
3
4
5
2
1
nuc = 0.50 ± 0.02
nuc = 0.47 ± 0.02
0
nuc = 0.47 ± 0.03
16
17
18
19
20
pKa + log p/q
Figure 1. Brønsted-type plots for aminolysis of 2,4-dinitrophenyl X-substituted-cinnamates in
MeCN at 25.0 ± 0.1 oC. X = 4-NO2 (1a, ▲); X = H (1c, ○); X = 4-MeO (1e, ●). The identity of
points is given in Table 1.
3
lg = 0.66
R2 = 0.996
2a
2
1
2b
0
2c
-1
2d
2e
-2
2f
2g
-3
-4
18
20
22
24
26
Y-PhOH
pKa
Figure 2. Brønsted-type plot for the reactions of Y-substituted-phenyl cinnamates (2a-2g) with
piperidine in MeCN at 25.0 ± 0.1 oC. The identity of points is given in Table 2.

Page 22 of 23
4
2
4
2
A
B
2a
2a
2b
2b
0
0
2c
2d
2c
2d
-2
-4
-6
-2
-4
-6
2e
2e
2f
2f
2g
2g
Y = 2.89
R2 = 0.990
Y = 3.67
R2 = 0.916
0.0
0.5
1.0
1.5
2.0
0.0
0.5
1.0
1.5
2.0


Figure 3. Hammett plots correlated with σ– (A) and σo constants (B) for the reactions of Y-
substituted-phenyl cinnamates (2a-2g) with piperidine in MeCN at 25.0 ± 0.1 oC. The identity of
points is given in Table 2.
3.0
 = 0.75
2.5
 = 1.38
 = 0.78
2.0
1.5
1.0
1a
 = 1.29
1b
 = 0.66
1c
1d
1e
1f
 = 1.18
-0.5
0.0
0.5
1.0

Figure 4. Hammett plots for reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-1f)
with piperidine (●), piperazine (□) and morpholine (○) in MeCN at 25.0 ± 0.1 oC. The identity of

Page 23 of 23
points is given in Table 3.
 = 0.71, r = 0.65
 = 0.70, r = 0.66
 = 0.62, r = 0.68
3.0
2.5
2.0
1.5
1.0
1a
1b
1c
1d
1e
1f
-1.0
-0.5
0.0
0.5
1.0
o + r (+-o)
Figure 5. Yukawa-Tsuno plots for reactions of 2,4-dinitrophenyl X-substituted-cinnamates (1a-
o
1f) with piperidine (●), piperazine (□), and morpholine (○) in MeCN at 25.0 ± 0.1 C. The
identity of points is given in Table 3.