Nucleofugality hierarchy, in the aminolysis reaction of 4-cyanophenyl 4-nitrophenyl carbonate and thionocarbonate. Experimental and theoretical study

Article abstract of DOI:10.1039/d0nj05837h

Nucleophilic substitution reactions of the title compounds have been investigated with a series of secondary alicyclic amines in several solvents. The solvent, amine, and electrophilic group effects on kinetics, mechanism and nucleofugality hierarchy are discussed from experimental and theoretical studies. These studies show the mechanistic dependence on the solvent polarity; the theoretical results indicate that the relative polarization of the reactive centres (CO and CS) and the stabilization of the nucleofuges are the main factors in the control of the product distribution.

Full text of DOI:10.1039/d0nj05837h

NJC
View Article Online
View Journal | View Issue
PAPER
Nucleofugality hierarchy, in the aminolysis
reaction of 4-cyanophenyl 4-nitrophenyl
carbonate and thionocarbonate.
Cite this: New J. Chem., 2021,
45, 11495
Experimental and theoretical study†
Rodrigo Montecinos, * Margarita E. Aliaga,
and Jose G. Santos
Paulina Pavez,
Patricio Cornejo
*
´
Nucleophilic substitution reactions of the title compounds have been investigated with a series of
secondary alicyclic amines in several solvents. The solvent, amine, and electrophilic group effects on
kinetics, mechanism and nucleofugality hierarchy are discussed from experimental and theoretical
studies. These studies show the mechanistic dependence on the solvent polarity; the theoretical results
indicate that the relative polarization of the reactive centres (CQO and CQS) and the stabilization of the
nucleofuges are the main factors in the control of the product distribution.
Received 30th November 2020,
Accepted 2nd June 2021
DOI: 10.1039/d0nj05837h
rsc.li/njc
O-(4-nitrophenyl) S-4-(nitrophenyl) thiol (1) and dithiocarbo-
nates (2) with secondary alicyclic amines (SAA), in aqueous
Introduction
Nucleofuge hierarchy has been established by the Mayr, Denegri ethanol, both phenoxides are nucleofuges,7b although the pKa
and Kronja groups,1 whose study involved a leaving group ability of 4-nitrophenol is three units greater than the pKa of 4-nitro-
scale based on the SN1 solvolysis reactions of benzhydryl derivatives, benzenethiol.7l
which yield a carbocation and the nucleofuge. However, despite the
In addition, the kinetic study of the reactions of 2 with a
large number of nucleofuge families tested,1a only a few phenols series of anilines shows that both (phenolate and benzenethio-
have been studied.2 As the rate constants of these reactions are late) are nucleofuges.7j However, in the pyridinolysis of 2, only
affected by the solvent, these nucleofugality values correspond to 4-nitrophenolate is the nucleofuge,7k suggesting that the nature
the nucleofuge–solvent pair.1,2
of the amine affects the relative nucleofugality of groups. Also,
In general, we are interested in the study of nucleofugality the aminolysis of S-phenyl and S-(4-chlorophenyl) O-(4-nitro-
hierarchies involved in nucleophilic reactions, e.g. nucleophilic phenyl) thiol (3 and 4) and dithiocarbonates (5 and 6)7d with
substitutions through an addition–elimination mechanism, in SAA provides evidence for the importance of the electrophilic
which nucleofuge departure is not necessarily involved in the group in the nucleofuge hierarchy (Scheme 1).
rate-determining step.
There have been several studies about nucleophilic reactions
The nucleophilic substitution reactions of carbonyl and of diaryl thionocarbonates, i.e. in the reactions of 4-cyano-
thiocarbonyl derivatives in a solution with reagents of varying phenyl 4-nitrophenyl thionocarbonate (7) with phenols7a and
nucleophilicity have been studied by several groups. In particular, SAA,7i in an aqueous ethanol solution, only 4-nitrophenolate
kinetic and mechanism studies of these processes have been fully ion is the nucleofuge, suggesting that the pKa is the reason for
described,3–7 but very few studies have been done on the nucleo- this behavior (the difference in the pKa is 0.98); nevertheless, in
fugality hierarchy in the nucleophilic reactions of diarylcarbonates the reactions of 4-cyanophenyl 3-nitrophenyl thionocarbonate
or its sulfur (thiol or thiono) and dithio analogs.
(8) with phenols,7a SAA and anilines,7c the expulsion of the two
In relation to the nucleophilic reactions of diarylthiol- and O-aryl groups was found, (the difference in the pKa is also 0.98).
diaryldithio carbonates, different nucleofuge families are involved In the phenolysis reaction of 8, the ratio 3-nitrophenolate/
(phenolates and benzenethiolates);7 some studies show that both 4-cyanophenolate is 1/3 while the ratio is 2/3 in the aminolysis,
groups are nucleofuges. For example, in the stepwise reaction of providing evidence for the importance of the electrophilic
group in the nucleofuge hierarchy.
In this work, we report the differences in the mechanism
of SAA aminolysis reactions for two very similar compounds,
´
Departamento de Quimica Fisica, Facultad de Quımica y de Farmacia,
´
Pontificia Universidad Catolica de Chile, Casilla 306, Santiago, Chile.
4-nitrophenyl 4-cyanophenyl thionocarbonate (7) and 4-nitro-
E-mail: rmontecinoe@uc.cl, jgsantos@uc.cl
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0nj05837h phenyl 4-cyanophenyl carbonate (9) in acetonitrile solution;
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11495

View Article Online
Paper
NJC
shows the presence of aromatic signals corresponding to 12, 13,
morpholine 4-cyanophenyl thionocarbamate (14) and morpho-
line 4-nitrophenyl thionocarbamate (15), which is also shown in
Scheme 3. These results demonstrate that the two O-aryl groups
are nucleofuges for both substrate reactions.
Kinetic spectrophotometric study was carried out, following
the spectral changes in the reaction cell (see Fig. S3–S6 in ESI†).
These reactions obey a first-order equation and pseudo-first-
order rate constants (kobs) were obtained (see Tables S1–S4 in
ESI†). kobs vs. [amine] plots are linear according eqn (1), where
k0 and kN are the rate coefficients for the substrates’ solvolysis
and aminolysis, respectively.
Scheme 1 Chemical structures of thiol and dithiocarbonates.
kobs = k0 + kN[amine]
(1)
The experimental conditions, amine concentrations and kobs
values obtained for reactions 7 and 9 with SAA in acetonitrile, at
25 1C, are shown in Tables S1 and S2, in the ESI.† The values of
k0 and kN were obtained as the intercept and slope, respectively,
from the linear plots of kobs against free amine concentration,
eqn (1). The k0 values were much lower than those of the kN
[amine] term in eqn (1). Table 1 shows the second-order rate
constants (kN) for reactions 7 and 9 with SAA and the pKa of
amines (pKa(ACN)) at 25 1C.
The Brønsted-type plot for the SAA aminolysis of thionocar-
bonate 7 and carbonate 9 in acetonitrile were obtained (Fig. 1)
using the data from Table 1. The kN values for the reactions
with piperazine were corrected because of the two amine
groups present in the nucleophile.10
Scheme 2 Chemical structures of thionocarbonates and carbonate.
in these cases, the two probable nucleofuges are from the same
family (4-nitro and 4-cyanophenolates) and the relative nucleo-
fugality for both phenolate ions and the influence of the solvent
in this relative nucleofugalities can be determined. In order to
obtain these objectives an experimental (kinetics and analyti-
cal) and a theoretical study of the reaction of 7 and 9 with
morpholine and piperidine were done (Scheme 2).
As shown in Fig. 1A, the Brønsted-type plot found for the
aminolysis of the thionocarbonate 7 is linear, with a slope b
value = 0.65. This b value is in agreement with those found for
similar concerted reactions (0.4–0.7).4,7e–h,11
Results and discussion
Kinetic and mechanism studies
Nonetheless, the b value by itself is not enough to conclude
that a mechanism is concerted. It is also necessary to make sure
that the expected pKa value at the center of the Brønsted
The 1H-NMR spectrum for the reaction of 9 with excess morpholine
in deuterated acetonitrile (see Fig. S1 in ESI†) shows the presence
of aromatic signals corresponding to morpholine 4-cyanophenyl
carbamate (10), morpholine 4-nitrophenyl carbamate (11),
4-nitrophenolate (12), and 4-cyanophenolate (13), as detailed in
Scheme 3.
À
Á
curvature pKaꢀ for a hypothetical stepwise mechanism is
within the pKa range used.11
For the aminolysis reactions of carbonates and their sulfur
derivatives reacting through a stepwise mechanism the pKaꢀ
In the same way, the 1H-NMR spectrum for the reaction of 7 with value is known to be greater than the pKa of the leaving group.
excess morpholine in deuterated acetonitrile (see Fig. S2 in ESI†) As the pKa of 4-nitrophenol and 4-cyanophenol, in acetonitrile,
Scheme 3 Products obtained from the reactions of 7 and 9 with morpholine in acetonitrile solutions.
11496
|
New J. Chem., 2021, 45, 11495–11505
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Paper
Table 1 Acidity constants (pKa(ACN)) and second-order rate constants (kN)
for reactions 7 and 9 with SAA in acetonitrile (ACN), at 25 1C
kN/sÀ1 MÀ1
6a,9
AMINES
pKa(ACN)
7
9
Morpholine
16.6
17.0
17.6
18.5
18.8
2.5 Æ 0.1
11.8 Æ 0.3
11.9 Æ 0.2
82.7 Æ 6
1.9 Æ 0.2
2.6 Æ 0.1
4.2 Æ 0.2
25.1 Æ 1
Formylpiperazine
1-(2-Hydroxyethyl)piperazine
Piperazine
Scheme 4 Proposed mechanism for the reaction of carbonate 9 with
SAA.
Piperidine
77.3 Æ 2
113.4 Æ 4
To understand the reactivity patterns and establish how the
nucleophile and electrophile structures affect the reaction
mechanisms, it is necessary to comprehend how the transition
state structures in the rate-determining steps contribute to
the dominant mechanistic pathway.7c,d Thus, thermodynamic
and/or kinetic factors can govern the distribution of products
for nucleophilic reactions.7d,14,15
Indeed, previous studies have demonstrated that the thermo-
dynamic factor, such as carbon basicity, has a negligible effect on
the energy barrier for the aminolysis reactions of dithio-, thiono-
carbonates and carbonates.7a,c,d Accordingly, we have studied
the most probable reaction mechanism using the aminolysis
reaction of thionocarbonate 7 and carbonate 9 with the nucleo-
philes morpholine and piperidine as reaction models. In the
case of the concerted pathway, the reaction consists of one step,
in which all bond-forming and -breaking processes occur
simultaneously. Thus, the transition state for the concerted
mechanism (cTS) involves the simultaneous creation of a C–N
Fig. 1 Brønsted-type plot for the reactions of SAA with 7 ( ; A) and 9
(K; B), in acetonitrile (ACN).
are 20.7 and 22.7, respectively,12 the pKaꢀ value in acetonitrile
would be expected to be greater than 20, which in this case is bond, cleavage of the C–O bond, and a proton transfer from the
outside the pKa range of the studied amines.
amino to the oxygen atom in the nucleofuge. Fig. 2 shows the
Therefore, if the mechanism were stepwise, the b = 0.65 of structures involved in the concerted pathway of the aminolysis
Fig. 1A would correspond to the expulsion of the leaving group for compound 7 with morpholine. Here, the morpholine nitro-
from a tetrahedral intermediate; however, the b value found is gen attacks the thiocarbonyl carbon in the compound 7, with
too small for this step, confirming the concerted mechanism. the simultaneous proton transfer from the morpholine nitrogen
Interestingly, the Brønsted plot obtained for aminolysis reac- toward the oxygen atom of the leaving groups in the transition
tion of 9, (Fig. 1B), is concave upward. In general, for this kind states cTS. The dashed lines indicate the broken/forming bonds
of nucleophilic substitution reactions, Brønsted plots are linear corresponding to the imaginary frequency found in the cTS.
or biphasic downward, derived from a change in the reaction Similar transition states have been reported for the aminolysis
rate determining step. A concave upward non-linear free energy of esters.16 Regarding the reaction model of morpholine with
correlation plot is not frequent and is considered to be a the thionocarbonate, the distance between the thiocarbonyl
diagnostic of a one reaction with two mechanistic pathways.13 carbon and the 4-cyanophenol oxygen (nucleofuge) in the
For instance, Cevasco et al. (1985)13f showed a concave upward transition state structure (cTS-7) is much longer, 2.26 Å, than
Brønsted plot (log k vs. pK(lg)) for the hydrolysis reaction of a that in compound 7, 1.35 Å; in the same way, the nitrogen–
series of substituted phenyl 4-hydroxybenzoates in aqueous carbon bond in the cTS-7 has a distance of 1.50 Å, which is
solutions. These results were explained by a BAc2 mechanism greater than the 1.32 Å observed in the thiocarbamate product.
change for poor leaving groups to an ElcB pathway for good Similarly, for the reaction of morpholine with carbonate 9, the
leaving groups. Therefore, the concave upward Brønsted-type distance between the carbonyl carbon and the 4-cyanophenol
plot for reaction of 9 with SAA of Fig. 1B would be associated oxygen (nucleofuge) in the concerted transition state structure
with the existence of two mechanisms, one concerted and one (cTS-9) is longer, 2.15 Å, than in compound 9, 1.35 Å, and the
stepwise, as is shown in Scheme 4, where kc is the concerted nitrogen–carbon bond in the cTS-9 has a distance of 1.50 Å,
way and k1 is the rate constant for the formation zwitterionic which is greater than the 1.35 Å observed in the corresponding
intermediate TÆ by the nucleophilic attack of the amine to the thiocarbamate product. The bond lengths of all structures are
carbonilic moiety of 9 (the stepwise way). Apparently, as the tabulated in Tables S7–S10 in the ESI.†
amine basicity increases, the stepwise mechanism is more
important.
On the other hand, the stepwise pathway for the aminolysis of
the compounds 7 and 9 corresponds to an addition–elimination
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11497

View Article Online
Paper
NJC
Fig. 2 Optimized structures along the concerted pathway for the aminolysis of compound 7 with morpholine in acetonitrile for the departure of 4-
cyanophenol. The dashed lines in the transition state structure cTS-7 indicates the normal coordinate with one imaginary frequency.
process. Fig. 3 shows the structures along the stepwise pathway stepwise proposal mechanism for the reaction of 9 with piperidine
for the aminolysis of compound 9 with piperidine. The first step and 4-nitrophenol and the corresponding carbamate as products.
of the reaction is the attack of the piperidine nitrogen on the The dashed lines correspond to the vibrational motion corres-
carbonyl carbon of the carbonate 9. This addition takes place ponding to an imaginary frequency in the first (TS1) and second
through a transition state TS1. In TS1, the CQO double bond transition state (TS2), respectively.
becomes slightly longer (1.21 Å) than in the carbonate 9 (1.20 Å).
Fig. 4 shows the relative Gibbs free energy profiles for
The new C–N bond created has a length of 1.38 Å in TS1 and stepwise and concerted pathway mechanisms for the aminolysis
1.45 Å for the intermediate TÆ. The second step corresponds of compounds 7 and 9 with both amines. Fig. 4 (upper) shows the
to the conversion of the tetrahedral intermediate into the resulting energy profiles for the reactions of compound 7 with
aminolysis products. The TÆ converts into the carbamates and morpholine (left) and with piperidine (right). The black lines are
phenol-derivative products through the transition state TS2. This associated to the reactants, the first transition state (TS1) and
second step involves breaking the C–O single bond and the intermediate (TÆ) in the stepwise pathway corresponding to the
rehybridization of the carbonyl carbon, accompanied by the nucleophilic attack of the morpholine or piperidine to the
nucleofuge expulsion and the proton transfer from the nitrogen thiocarbonyl or carbonyl groups in the compounds 7 and 9,
atom to the oxygen atom in the nucleofuge. Fig. 3 shows the respectively. The red lines represent the transition state associated
Fig. 3 Structures for the stepwise pathway for the aminolysis of compounds 9 with piperidine in acetonitrile. TS1 is the transition state between
reactants and the zwitterion tetrahedral intermediate TÆ. TS2 is the transition state between TÆ and 4-nitrophenol and the corresponding carbamate as
products. The dashed lines in the transition state structures indicate the normal coordinate with one imaginary frequency.
11498
|
New J. Chem., 2021, 45, 11495–11505
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Paper
to the departure of 4-nitrophenol group for concerted (CTS) and the experimental result in terms of the change of mechanism for
stepwise (TS2), while blue lines are used for TS2 associated to the the reaction of 9 from a concerted pathway with morpholine to a
departure of 4-cyanophenol group. For the reactions of 7 and 9 stepwise pathway with piperidine. Furthermore, in all the systems
with morpholine (Fig. 4 left), three of the four transition states studied, the relative energies for the departure of the nucleofuge
obtained from the concerted mechanism present lower energy from the corresponding TS were higher for the expulsion of
than those observed for the corresponding TS2. These results 4-cyanophenol (see Tables S11 and S12 in ESI†). These results,
indicate that both compounds 7 and 9 react with morpholine, also, predict a higher nucleofugality for 4-nitrophenol compared
preferentially following a concerted mechanism. Interestingly, the with 4-cyanophenol for these systems.
comparison of the transition state energies for reactions 7, and 9
The analysis of the bond distances for the different structures
with piperidine show a different behavior (Fig. 4 right). For the for the reactions of compounds 7 and 9 with piperidine or
reaction of 7 with piperidine, CTS associated to the departure of morpholine, including transition states, shows no significant
4-nitrophenol presents lower energy than TS2, as was observed for changes that satisfactorily explain the observed change of
the reaction models with morpholine. Nevertheless, in the reaction mechanisms (see Tables S7–S10 in ESI†). Therefore, we studied
of 9 with piperidine (Fig. 4, (lower-right)), TS2 for the departure of the molecular charge distribution using the molecular electro-
4-nitrophenol presents a lower energy level than that observed for static potential (MEP) for the reaction models. The colors from
CTS, favoring the stepwise mechanism, and confirming the red to blue in MEP surface are related to high and low electron
change of mechanism for this reaction. These results agree with density regions, respectively. Fig. 5A and B, show the MEP surface
Fig. 4 Relative Gibbs free energy profiles for aminolysis reactions, in acetonitrile, for the thionocarbonate 7 (upper) and carbonate 9 (lower). Left: Energy
profiles for the reaction with morpholine. Right: Energy profiles for the reaction with piperidine. Black lines are associated to the reactants (R), first
transition state (TS1) and intermediate (TÆ) in the stepwise pathway. Red lines represent the transition state associated with the departure of
4-nitrophenol group in CTS and TS2. Blue lines are related to the departure of 4-cyanophenol group in CTS and TS2. For simplicity products energies
are not shown in the profiles.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11499

View Article Online
Paper
NJC
obtained for the compounds thionocarbonate 7 and carbonate 9, we can infer that structures with a low polarization in the TS
respectively. From these figures, it is possible to observe an would favor the concerted pathway. Likewise, the nature of the
intense red color in the central region for carbonate 9, where amine does not modify the low polarization of the C–S reactive
the CQO group is located. This result indicates that the CQO center in the TS, showing that, for this reaction, there is no
group presents a high electronic polarization, while the CQS strong dependence on the properties of the nucleophile, but
(Fig. 5A) shows a weak polarization on these atoms. On the other rather it is the electrophile (CQS) that, with its low polarity,
hand, the MEP maps of the transition states for thionocarbonate would govern the nucleofuge departure.17,18 On the other hand,
with morpholine and piperidine (Fig. 5C and E, respectively) the MEP maps for the TSs of compound 9 with morpholine and
show a lower polarization of the C–S reactive center in comparison piperidine (Fig. 5D and F, respectively) exhibit an interesting
with the reactive center of the carbonate 7 (Fig. 5D and F, difference. For the reaction of compound 9 with morpholine,
respectively). Considering that compound 7 reacts with the the reactive center has a less intense red zone than that
nucleophiles, preferentially, through a concerted mechanism, observed for the reaction with piperidine. Hence, the carbonyl
Fig. 5 MEP surfaces mapped onto the isodensity surface for the molecule (A) thionocarbonate 7; (B) carbonate 9; (C) TS2: thionocarbonate
7-morpholine; (D) TS2: carbonate 9-morpholine; (E) TS2: thionocarbonate 7-piperidine; (F) TS2: carbonate 9-piperidine. All MEP surfaces were
calculated at the M06-2X/6-31G++(d,p) theory level in acetonitrile (CPCM).
11500
|
New J. Chem., 2021, 45, 11495–11505
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Paper
Table 2 Nucleophilic rate constants kN for the reaction of 7 and 9 with
piperidine in different solvents, Reichardt solvent polarity parameter
(ET(30))14 and Catalan’s solvent properties (SPP, SB, and SA)22
region of 9 with morpholine shows a reduced polarization than
that observed with piperidine. In addition, Fig. 5F shows the
MEP map with the highest electronic density on the 4-nitro-
phenolate fragment (nucleofuge). Therefore, the concerted reaction
mechanism would be associated with less polarized transition
states,19 while the stepwise mechanism would be related to more
polarized transition states. In the same way, the nature of the amine
modifies the polarization of the CO reactive center in TS2 (Fig. 5D
and F), and it cannot be ruled out for this reaction that both the
electrophile polarization and the nucleophilic nature of the amine
participates in the nucleofuge departure. Therefore, the stabilization
of the reactive group (CQO or CQS and their intermediates)
becomes an important parameter for establishing a preferential
reaction mechanism.18,20
kN/sÀ1 MÀ1
Solvent parameters
ET(30)b SPPc SBc SAc
Solvent
7
9
Toluene
Dioxane
Ethyl acetate
3.9 Æ 0.1 18.9 Æ 0.5 33.9 0.655 0.128
0
0
0
5.9 Æ 0.1
28 Æ 1
52 Æ 2
—
36.0 0.701 0.444
38.9 0.795 0.542
23.2 Æ 0.6
2-Methyl propanol 6.6 Æ 0.2
48.6 0.832 0.828 0.311
48.4 0.848 0.83 0.283
51.9 0.853 0.658 0.400
55.4 0.857 0.545 0.605
42.2 0.881 0.475
45.6 0.895 0.286 0.044
Isopropanol
Ethanol
9.2 Æ 0.2
8.9 Æ 0.4
4.6 Æ 0.2
70 Æ 2
67 Æ 3
52 Æ 3
65 Æ 2
190 Æ 10
Methanol
Acetone
Acetontrile
DMSO
0
79 Æ 2a 114 Æ 4a
500 Æ 20 3800 Æ 300 45.1 1.00 0.647 0.072
a
b
Value of Table 1. ET(30) is the Dimroth–Reichardt polarity scale.
(SA, SB and SPP are Catalan’s solvent properties such as the acidity,
c
Solvent effect studies
basicity, and polarizability, respectively).
It is interesting to note that the analysis of the products of the
reaction of 7 with morpholine, in aqueous ethanol,7i demon-
strates that only 4-nitrophenolate is the nucleofuge. The different
behaviors of the reaction in aqueous ethanol and in acetonitrile
could be attributed to a change in the reaction mechanism, as the
first mechanism is stepwise,7i while in the latter (this study), the
mechanism is concerted. The change of mechanism induced by
the change of solvent from polar to less polar can be explained by
the great destabilization of the zwitterionic tetrahedral intermedi-
ate. In addition, to have a global picture of the solvation effect on
the mechanism, the linear free energy relationship (LFER) can
provide a good tool to describe solute–solvent interactions.21
Thus, a solvent-dependent physicochemical property, such as a
rate constant, can be correlated with solvation properties of the
solvent, such as acidity (HBD solvents), basicity (nonpolar non-
HBD solvents) and the polarizability (dipolar non HBD solvents)
by using a multiparametric equation. In order to understand the
solvent effect in the title reaction in greater depth, we kinetically
studied the reaction of 7 and 9 with piperidine in several solvents,
with different solvation properties (i) nonpolar solvents (toluene,
nucleophilic rate constants for reactions 7 and 9 with piperidine
(Table 2), a multiparametric analysis23 was performed using
eqn (2) with the Catalan’s parameters (Table 2) (SA, SB and SPP
are the acidity, basicity and polarizability, respectively).
log kN = A0 + b  SPP + c  SA + d  SB
(2)
The multiparametric approaches for the solvent effects on the
piperidinolysis reaction of 7 lead to the equations shown in
Table S5 in ESI.†
Any parameter alone correlates with the experimental results.
The best correlation with two parameters was that involving the
dipolarity/polarizability SPP and acidity SA parameters according
to eqn (3) (eqn (S6), in Table S5 in ESI†).
log kN = À(3.7 Æ 0.4) + (6.4 Æ 0.5) Â SPP À (2.0 Æ 0.2) Â SA
(3)
dioxane), (ii) polar aprotic solvents (acetonitrile, acetone, DMSO, The incorporation of the solvent basicity (SB) leads to eqn (S7)
ethyl acetate) and (iii) polar protic solvents (methanol, ethanol, in Table S5 in ESI,† which increases the R value; however, there
2-propanol, 2-methyl propanol). The experimental conditions is a decrease in statistical F factor, and also, the standard error
and the pseudo-first-order rate constants are summarized in in the calculated SB coefficient is too large. Therefore, we
Tables S3 and S4, in ESI.† Table 2 summarizes the nucleophilic believe that the solvent basicity is not an important factor in
rate constants kN for the reaction of 7 and 9 with piperidine in the studied reactions. Fig. 6 shows a double logarithmic plot of
different solvents, showing an important solvent effect. For the experimental nucleophilic rate constant (kN(exp)) values
example, for these reactions, the k value increase of about 130 against those calculated by eqn (3) (kN(calc)). The plot shows,
and 200 times for 7 and 9, respectively, by going from toluene to within the experimental errors, a slope = 1 and intercept at the
DMSO as solvent.
origin, as expected for a good correlation.
In a first attempt to understand the solvent effect, we only
The most important contribution to enhancing the rate
used the Reichard ET(30)14 parameter of Table 2. Fig. S3, in ESI,† constant of this reaction is the solvent dipolarity/polarizability
shows the dependence of log kN against ET(30) for reactions 7 (SPP), while increasing solvent acidity (SA) decreases the rate
and 9 with piperidine in different solvents; it can be observed constant. The positive coefficient of SPP in eqn (3) is in accordance
that the log kN values initially increase with ET(30) solvents but with a greater TS stabilization than reactants, leading to less
for alcohols (polar protic solvents) the reaction rate decreases. activation energy and consequently an increase in the rate constant.
Further correlations revealed which parameters have the most
important impact.
On the other hand, the negative value of the solvent acidity
(SA) coefficient in eqn (3) is in accordance with the ability to
Thus, in order to have a better understanding of solvent donate hydrogen-bonds that would act on the nucleophile/
effects and to estimate the separate contributions to the electrophile pair, solvating the nucleophile by hydrogen-bond;8
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11501

View Article Online
Paper
NJC
from a concerted mechanism in non-aqueous solvents (this
study) to one stepwise in 44 wt% ethanol–water.7i
Nucleofugality
Taking into account the fact that the aminolysis reaction of 7
undergoes a change of mechanism from concerted to stepwise
when changing the solvent from acetonitrile to 44% p/p
aqueous ethanol and that in the latter only 4-nitrophenol
behaves as a nucleofuge, the influence of the solvent on the
ratio of nucleofuges in the aminolysis reaction of 7 and 9 was
1
assessed. For this purpose, the series of H-NMR spectra were
measured for the reactions of 7 and 9 with morpholine and
piperidine. These are shown in the Fig. S8–S17 in ESI.† In
addition, Table 3 shows the proportion of nucleofuges, (P)
determined from the ratio of the integration of aromatic proton
signals neighboring the nitro group into nitrophenol and
nitrophenyl thiocarbamate, respectively.
Fig. 6 Double logarithmic plot of kN(exp) vs. kN(calc by eqn (3)) for the
piperidinolysis of 7.
this effect would increase the activation energy of the reaction,
and therefore, decrease the rate constant.
Firstly, in the reactions of 7 with morpholine, in all the
solvents studied, 4-nitrophenolate ion always behaves as a
The solvent effect found is according to that observed for the better nucleofuge than 4-cyanophenolate ion (P 4 1). It is
concerted reaction of O-ethyl S-(2,4-dinitrophenyl) dithiocarbo- important to note that the calculation, based on the energy
nate with morpholine24 in which the increase in solvent polar- barriers (see Fig. 4), allows us to predict the experimental result
ity (SPP) has a positive effect on the second order rate constant, for the preferential product formation of 4-nitrophenol over 4-
while that of the acidity (SA) solvent parameter has a negative cyanophenol in acetonitrile. The preferential product for-
effect on it.
mation can be explained by the capacity of the nitro- as
The same statistical study was carried out for the reaction of electron-attractor group that induces a more efficient electronic
9 with piperidine in the different solvents studied (see Table S6 delocalization in the 4-nitrophenolates than the nitrile-group in
in ESI†).
4-cyanophenolates, in line with the sigma Hammett values.
From the multiparametric statistical study of the reaction of Therefore, the charge stabilization in the leaving groups, in
the piperidinolysis for carbonate 9, the best correlation with acetonitrile, could be the main factor that governs the product
two parameters (R = 0.88) is that of eqn (4) (eqn (S13) Table S6 distribution.
in ESI†).
It is also important to state that, within the error in the
experimental measurement, the solvent does not affect the
products’ relation (P value was keep between 2.1 and 2.5).
This result suggests that the relative nucleofugalities are inde-
log kN = À1.4 + 4.1 Â SPP À 0.6 Â SA
(4)
Nevertheless, we must disregard eqn (4) as a solution, because pendent of the solvent. There is also a similar quotient (P = 2.7)
the double logarithmic graph of kN (exp) vs. kN (calc by eqn (S13) for the piperidinolysis reaction of 7 in acetonitrile. This result
Table S6 in ESI†), not shown, presents a slope = 0.538 and an suggests that the nucleofuge hierarchy does not change in the
intersection = 0.88, far from the slope = 1 and null intercept amine series.
required.
On the other hand, in the reaction of 9 with morpholine in
Clearly this solvent behavior is not the same as shown by the acetonitrile, the nucleofugality ratio value (P = 1.7) is not
piperidinolysis of thionocarbonate 7; probably the piperidino- different than that for the substrate 7 (P = 2.4 in Table 3),
lysis reaction of carbonate 9 proceeds by two mechanistic probably because the reactions of both substrates with mor-
pathways, depending on the solvents. For this reaction, as pholine goes by a concerted mechanism. Nevertheless, in
shown above, the theoretical calculation indicates that the the reaction of 9 with piperidine in acetonitrile (P = 13.3),
barrier for TS2 is lower than TS for concerted mechanism.
(see Fig. S17, ESI†), this large increase in P can be seen in the
The change in the mechanism found for the piperidinolysis nucleofuge ability of 4-nitrophenol, relative to 4-cyanophenol,
reaction of carbonate 9 by increasing the polarity of the solvent probably due to the change of mechanism from concerted to
is in line with that found for thiocarbonate 7, which changes stepwise.
Table 3 Relative nucleofugality 4-nitrophenol/4-cyanophenol (P) in the reaction of 7 with morpholine in different deuterated and nondeuterated
solvents
Solvent
THF-d4
2.1
DMSO-d6
2.5
Acetone-d6
2.5
CD3CN
2.4
CD3OD
2.1
CDCl3
2.1
CH3OH
2.4
Acetone
2.4
CH3CN
2.3
P
11502
|
New J. Chem., 2021, 45, 11495–11505
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Paper
Conclusions
In all cases, under amine excess, pseudo-first-order rate
coefficients (kobs) were obtained adjusting the experimental
absorbance time curves to a first order kinetic equation
(see the calculated curves in Fig. S3–S6, ESI†). The nucleophilic
rate constants (kN) were determined from the slopes of linear
plots of kobs vs. amine concentration.
The reaction of thionocarbonate 7 with SAA in acetonitrile
solution presents a linear BrØnsted plot with b = 0.59, in line
with a concerted mechanism. This was corroborated by the
theoretical study in implicit acetonitrile model as solvent.
Nevertheless, the concave upward Brønsted plot for the reaction
of 9 with SAA in acetonitrile solution is consistent with two
mechanistic reaction paths, one concerted and other stepwise,
revealing a change of the reaction mechanism. The theoretical
Product studies
High performance liquid chromatography (HPLC). These
were carried out by a diode array detector, provided with
LiChroCARTs250-4 HPLC-RP-18e (5 mm) HPLC Cartridge
LiCrhorspheres100 RP 8, mobile phase 50% v/v CH3CN: phosphate
buffer (0.01 M/pH = 7.00), flow rate 1.5 mL/min. The products were
identified by comparison of their spectra and retention times (r.t.)
with those of authentic samples (see Fig. S18 in ESI†).
study predicts
a concerted pathway for the reaction of
compound 9 with morpholine and, alternatively, the stepwise
pathway would be the preferential mechanism for the reaction
of 9 with piperidine.
The solvent behavior found for the piperidinolysis of 7 is as
expected for a concerted mechanism; the increase in the solvent
polarity (SPP) boosts the second order rate constant and the
increase in acidity solvent (SA) decreases it. The theoretical
results predict concerted mechanisms for the aminolysis of
both thionocarbonate 7 and carbonate 9 with morpholine in
the acetonitrile as solvent.
In the reactions of 7 with morpholine in the different solvents,
both aryloxy groups are nucleofuges and the 4-nitrophenolate ion
nucleofugality is greater than that of 4-cyanophenolate ion, the
products’ relation (P = 2.1–2.5). This result suggests that the
relative nucleofugalities are independent of the solvent. There is
also a similar quotient (P = 2.7) for the piperidinolysis reaction of 7
in acetonitrile. This result suggests that the nucleofuge hierarchy
does not change in the amine series. All these reactions are
concerted. These results are also predicted by the theoretical study.
The relative nucleofugality 4-nitrophenol/4-cyanophenol in
the reaction of 9 with morpholine and piperidine in acetonitrile
changes from 2.7 to 13.2, due to the change of mechanism from
concerted to stepwise. In summary, from the results of this study we
can conclude that the use of nucleofugality scales is conditioned by
the reaction mechanism, rather than by the solvent used.
Nuclear magnetic resonance
In order to determine the products of the studied reactions,
1H-NMR spectra were obtained on an AM-400 instrument in
1H-NMR signals in the aromatic region of the reactions of
substrates and those for the expected products for the reactions
were assigned by comparison with those of authentic samples.
The expected products 10, 11, 14 and 15 were prepared in situ
by the reactions of 4-cyanophenyl chloroformate, 4-nitrophenyl
chloroformate, 4-cyanophenyl chlorothioformate and 4-nitro-
phenyl chlorothioformate with morpholine, respectively.
Theoretical methods
DFT calculations were carried out in order to explain the origins
of the mechanism change and nucleofuge hierarchy for the
reaction models. In particular, the studies consider the analysis
of concerted and stepwise pathways for the reactions of thiono-
carbonate 7 and carbonate 9 with morpholine and piperidine.
DFT calculations were performed with the GAUSSIAN 09
program package.27 All reactants, products, intermediates, and
transition state structures were optimized at the M06-2X level of
theory using the 6-31G++(d,p) basis set. All the optimizations
were carried out in acetonitrile by using the polarized con-
tinuum model (SCRF = CPCM).28 The search for each lowest
energy of the reactants, zwitterionic tetrahedral intermediate
and products were manually changing the initial geometries
and by comparing the resulting optimized structures and
energies using a theory/basis set at the M06-2X/6-31G++(d,p)
level. Similar procedures for locating the lowest energy struc-
tures have been reported in previous works.7c,d
Experimental
Materials
Secondary alicyclic amines (SAA) were purified by recrystallization
or distillation. The thionocarbonate 7 was prepared by a literature
method7i,25 and identified by 1H NMR and IR analyses.7i
The carbonate 9 was prepared by a literature method25 and
1
identified by H NMR and 13C NMR analyses.26
To verify the nature of stationary points, vibrational frequency
computations were carried out at the same level of theory. Transi-
tion states were verified by obtaining only one imaginary frequency
at the same level of theory. CYLView software was used for the
visualization of structures involved in the reaction mechanism.29
Kinetic measurements
The kinetics of the reactions were analyzed through a diode
array spectrophotometer; some representative examples are pre-
sented in Fig. S3–S6 (ESI†), following the absorbance increase at a
wavelength where the change was greater (see experimental curves
in Fig. S3–S6, ESI†). All reactions were studied at 25.0 Æ 0.1 1C,
under at least a 10-fold amine excess over the substrate, with the
initial concentration of the latter being 2.7 Â 10À5 M and 3.0 Â
10À5 M for the reactions of 7 and 9, respectively.
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11503

View Article Online
Paper
NJC
2009, 74, 6374–6377; (h) E. A. Castro, M. Cubillos, R. Iglesias
and J. G. Santos, Int. J. Chem. Kinet., 2012, 44, 604–611; (i) E. A.
Castro, L. Leandro, N. Quesieh and J. G. Santos, J. Org. Chem.,
2001, 66, 6130–6135; ( j) J. G. Santos and M. Gazitu´a, J. Phys.
Org. Chem., 2019, 32, e3818; (k) E. A. Castro, M. E. Aliaga,
M. Gazitu´a and J. G. Santos, J. Phys. Org. Chem., 2012, 25,
994–997; (l) E. A. Castro, M. Cepeda, P. Pavez and J. G. Santos,
J. Phys. Org. Chem., 2009, 22, 454–459.
8 A. Albert and E. P. Serjeant, The Determination of Ionization,
Constants Chapman and Hall, London, 1971, p. 87.
9 W. J. Spillane, P. McGrath, D. Brack and A. B. O’Byrne,
J. Org. Chem., 2001, 66, 6313–6316.
10 R. P. Bell, The proton in chemistry, Cornell University Press,
1973.
11 E. Chystiuk and A. Williams, J. Am. Chem. Soc., 1987, 109,
3040–3046; A. Williams, Acc. Chem. Res., 1989, 22, 387–392;
S. Ba-Saif, A. K. Luthra and A. Williams, J. Am. Chem. Soc.,
1989, 111, 2647–2652.
12 I. M. Kolthoff and M. K. Chantooni Jr, J. Am. Chem. Soc.,
1969, 91, 4621–4625; J. Magonsky, Z. Paulak and T. Jasinsky,
J. Chem. Soc., Faraday Trans., 1993, 89, 119–122; F. Eckert,
I. Leito, I. Kaljurand, A. Kutt, A. Klamt and M. Diedenhofen,
J. Comput. Chem., 2009, 30, 799–810.
13 (a) K. K. Adhikary and H. W. Lee, Bull. Korean Chem. Soc.,
2011, 32, 857–862; (b) N. El Guesmi, G. Berionni and
B. H. Asghar, Monatsh. Chem., 2013, 144, 1537–1545;
(c) M. E. U. Hoque and H. W. Lee, Bull. Korean Chem. Soc.,
2012, 33, 325–328; (d) M. E. U. Hoque, N. K. Dey, A. K. Guha,
C. K. Kim, B. S. Lee and H. W. Lee, Bull. Korean Chem. Soc.,
2007, 28, 1797; (e) H. R. Barai and H. W. Lee, Bull. Korean
Chem. Soc., 2012, 33, 309–312; ( f ) G. Cevasco, G. Guanti,
A. R. Hopkins, S. Thea and A. Williams, J. Org. Chem., 1985,
50, 479–484.
14 H. Mayr and A. R. Ofial, Acc. Chem. Res., 2016, 49, 952–965.
15 J. Hine and R. D. Weimar, J. Am. Chem. Soc., 1965, 87,
3387–3396.
16 S. Ilieva, B. Galabov, D. G. Musaev, K. Morokuma and
H. F. Schaefer III, J. Org. Chem., 2003, 68, 1496–1502.
17 T. A. Hamlin, M. Swart and F. M. Bickelhaupt, ChemPhysChem,
2018, 19, 1315–1330.
Acknowledgements
This work was support by FONDECYT grants 1160271, 1170976
and 1171870. Powered@NLHPC: this research was partially
supported by the supercomputing infrastructure of the NLHPC
(ECM-02).
References
1 (a) N. Streidl, B. Denegri, O. Kronja and H. Mayr, Acc. Chem.
Res., 2010, 43, 1537–1549; (b) B. Denegri, A. R. Ofial, S. Juri,
A. Streiter, O. Kronja and H. Mayr, Chem. – Eur. J., 2006, 12,
1648–1656.
2 (a) M. Matic, B. Denegri and O. Kronja, Eur. J. Org. Chem.,
2010, 6019–6024; (b) M. Matic, N. Bebek, B. Denegri and
O. Kronja, Croat. Chem. Acta, 2016, 89, 355–362; (c) B. Denegri,
M. Matic and O. Kronja, Synthesis, 2017, 3422–3432;
(d) R. J. Mayer, M. Breugst, N. Hampel, A. R. Ofial and
H. Mayr, J. Org. Chem., 2019, 84, 8837–8858.
3 E. A. Castro, Chem. Rev., 1999, 99, 3505–3524, and refer-
ences therein.
4 A. Williams, Chem. Soc. Rev., 1994, 93–100; A. Williams,
Concerted Organic and Bio-Organic Mechanisms, CRC Press,
Boca Raton, FL, 2000; A. Williams, Free energy relationships
in organic and bioorganic chemistry, RSC, Cambridge, 2003.
5 W. P. Jencks, Catalysis in Chemistry and Enzymology, McGraw-
Hill, New York, 1969; W. P. Jencks and M. Gilchrist, J. Am.
Chem. Soc., 1968, 90, 2622–2637; B. D. Song and W. P. Jencks,
J. Am. Chem. Soc., 1989, 111, 8479–8484; J. P. Fox and W. P.
Jencks, J. Am. Chem. Soc., 1974, 96, 1436–1449; A. C.
Satterthwait and W. P. Jencks, J. Am. Chem. Soc., 1974, 96,
7018–7031; M. J. Gresser and W. P. Jencks, J. Am. Chem. Soc.,
1977, 99, 6963–6970; M. J. Gresser and W. P. Jencks, J. Am.
Chem. Soc., 1977, 99, 6970–6980.
6 (a) I.-H. Um, H.-W. Yoon, J.-S. Lee, H.-J. Moon and D.-S.
Kwon, J. Org. Chem., 1997, 62, 5939–5944; (b) I.-H. Um,
K.-H. Kim, H.-R. Park, M. Fujio and Y. Tsuno, J. Org. Chem.,
2004, 69, 3937–3942; (c) I.-H. Um, Y.-M. Fujio, M. Park,
M. Mishima and Y. Tsuno, J. Org. Chem., 2007, 72,
4816–4821; (d) I.-H. Um and A.-R. Bae, J. Org. Chem., 2011,
76, 7510–7515; (e) I.-H. Um, A.-R. Bae and T.-I. Um, J. Org.
Chem., 2014, 79, 1206–1212; ( f ) I.-H. Um, M.-Y. Kim,
A.-R. Bae, J. M. Dust and E. Buncel, J. Org. Chem., 2015,
80, 217–222; (g) I.-H. Um, J.-H. Song, A.-R. Bae and
J. M. Dust, Can. J. Chem., 2018, 96, 1011–1020.
18 A. R. Katritzky, O. Meth-Cohn and C. H. Rees, Comprehensive
Organic Functional Group Transformations, Synthesis: Carbon
with One Heteroatom Attached by a Multiple Bond, Elsevier,
2003, vol. 3.
19 M. Alves, R. Mereau, B. Grignard, C. Detrembleur, C. Jerome
and T. Tassaing, RSC Adv., 2017, 7, 18993–19001.
20 M. Y. Kim and I. H. Um, Bull. Korean Chem. Soc., 2016, 37,
1401–1405.
˜
´
7 (a) E. A. Castro, A. Canete, P. R. Campodonico, M. Cepeda,
P. Pavez, R. Contreras and J. G. Santos, Chem. Phys. Lett.,
2013, 572, 130–135; (b) E. A. Castro, M. E. Aliaga, M. Gazitu´a,
P. Pavez and J. G. Santos, J. Phys. Org. Chem., 2014, 27,
265–268; (c) R. Montecinos, M. E. Aliaga, P. Pavez and J. G.
Santos, New J. Chem., 2017, 41, 9954–9962; (d) R. Montecinos,
M. Gazitu´a and J. G. Santos, New J. Chem., 2019, 43, 6372–6379;
21 C. Reichardt and T. Welton, Solvents and Solvent Effects in
Organic Chemistry, Wiley VCH Verlag & Co., Weinheim,
German, 4th edn, 2011.
´
´
´
22 J. Catalan, V. Lopez, P. Perez, R. Martin-Villamil and J. G.
´
´
Rodriguez, Liebigs Ann., 1995, 241–252; J. Catalan, C. Dıaz,
´
(e) E. A. Castro, M. Aliaga, P. Campodonico and J. G. Santos,
´
´
V. Lopez, P. Perez, J. L. G. De Paz and J. G. Rodriguez, Liebigs
J. Org. Chem., 2002, 67, 8911–8916; ( f ) E. A. Castro, M. Gazitu´a
and J. G. Santos, J. Org. Chem., 2005, 70, 8088–8092;
(g) E. A. Castro, M. Ramos and J. G. Santos, J. Org. Chem.,
´
´
Ann., 1996, 1785–1794; J. Catalan and C. Dıaz, Liebigs Ann.,
1997, 1941–1949.
11504
|
New J. Chem., 2021, 45, 11495–11505
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Paper
23 I. A. Koppel and V. A. Palm, in Advances in linear free energy
relationships, ed. N.V. Chapman and J. Shorter, Plenum
Press, New York, 1972, p. 222.
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, M. J. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox,
Gaussian09, Revision D.01, Gaussian, Inc., Wallingford, CT,
2013.
´
24 D. Millan, J. G. Santos and E. A. Castro, J. Phys. Org. Chem.,
2012, 25, 989–993.
25 H. R. Al-Kazimi, D. S. Tarbel and D. A. Plant, J. Am. Chem.
Soc., 1955, 77, 2479–2482.
´
26 J. G. Santos, M. E. Aliaga, M. F. Marquez and M. Oyarzu´n,
J. Phys. Org. Chem., 2019, 32, e3845.
27 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
´
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, 28 M. Garcia-Rates and F. J. Neese, Comput. Chem., 2020, 41,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, 922–939.
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, 29 C. Y. Legault, CYLview20, Universite de Sherbrooke, 2020.
H. Nakai, T. Vreven, J. A. Montgomery Jr, J. E. Peralta, http://www.cylview.org.
´
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 11495–11505 | 11505