Nucleophilic Fluorination with KF Catalyzed by 18-Crown-6 and Bulky Diols: A Theoretical and Experimental Study

Article abstract of DOI:10.1021/acs.joc.0c02229

The activation of potassium fluoride for nucleophilic fluorination of alkyl halides is an important challenge because of the high lattice energy of this salt and its low solubility in many polar aprotic solvents. Crown ethers have been used for increasing the solubilization of KF during several decades. Nevertheless, these macrocycles are not enough to produce a high reaction rate. In this work, theoretical methods were used for designing a synergic combination of bulky diols with crown ethers able to accelerate this kind of reaction. The calculations have predicted that the bulky diol 1,4-Bis(2-hydroxy-2-propyl)benzene, which has distant hydroxyl groups, is able to catalyze nucleophilic fluorination in combination with 18-crown-6 via two hydrogen bonds to the SN2 transition state. Experimental studies following the theoretical predictions have confirmed the catalytic effect and the estimated kinetic data point out that the bulky diol at 1 mol L-1 in combination with 18-crown-6 is able to produce an 18-fold increase in the reaction rate in relation to crown ether catalysis only. The reaction produces 46% yield of fluorination after 24 h at moderate temperature of 82 °C, with minimal formation of the side elimination product. Thus, this work presents an improved method for fluorination with KF salt.

Full text of DOI:10.1021/acs.joc.0c02229

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Article
Nucleophilic Fluorination with KF Catalyzed by 18-Crown‑6 and
Bulky Diols: A Theoretical and Experimental Study
Samuel L. Silva, Marcelo S. Valle, and Josefredo R. Pliego, Jr*
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ABSTRACT: The activation of potassium fluoride for nucleophilic fluorination of alkyl halides is
an important challenge because of the high lattice energy of this salt and its low solubility in many
polar aprotic solvents. Crown ethers have been used for increasing the solubilization of KF during
several decades. Nevertheless, these macrocycles are not enough to produce a high reaction rate.
In this work, theoretical methods were used for designing a synergic combination of bulky diols
with crown ethers able to accelerate this kind of reaction. The calculations have predicted that
the bulky diol 1,4-Bis(2-hydroxy-2-propyl)benzene, which has distant hydroxyl groups, is able to
catalyze nucleophilic fluorination in combination with 18-crown-6 via two hydrogen bonds to the
SN2 transition state. Experimental studies following the theoretical predictions have confirmed
the catalytic effect and the estimated kinetic data point out that the bulky diol at 1 mol L−1 in combination with 18-crown-6 is able to
produce an 18-fold increase in the reaction rate in relation to crown ether catalysis only. The reaction produces 46% yield of
fluorination after 24 h at moderate temperature of 82 °C, with minimal formation of the side elimination product. Thus, this work
presents an improved method for fluorination with KF salt.
catalysis. More recently, theoretical calculations have shown
that a new crown ether modified with addition of thiourea
groups (thiourea-crown-ether) is very effective for solubilizing
and activating KF, even overcoming the [2.2.2]-cryptand.17
An important concept in the designing of more effective
supramolecular catalysts for nucleophilic fluorination is the
idea that the hydrogen bonds should involve the incoming and
leaving groups in the SN2 transition state.18,19 This effect that
was predicted early by theoretical calculations and an
envisioned molecule, 1,4-benzenedimethanol (BDM, Figure
1), would have hydroxyl groups in adequate positions for
promoting the catalysis.19 However, due to the formation of
aggregates in the solution phase, this effect could be difficult to
observe with 1,4-benzenedimethanol.18 For another structures
able to avoid dimerization, such as the BACCA (Figure 1),
such an effect is important for explaining quantitatively the
observed catalysis.13,15,20
INTRODUCTION
■
Fluorination of aliphatic compounds using fluoride salts as a
fluorine source has had an important advance in the past 15
years.1,2 The discovered bulky alcohols as tert-butanol that are
more efficient than polar aprotic solvents such as acetonitrile
and dimethylformamide for promoting fluorination with CsF
salt have shown that both interactions of the solvent with
cations and anions are important for accelerating the
reaction.3−5 This different view from the classical paradigm
that less anion solvation that leads to a higher reaction rate6 is
due to an important aspect of this reaction: the MF salt has low
solubility. Thus, the solvent must have an enough high
interaction with the MF salt to overcome the lattice energy in
the ionic solid.7 At the same time, this interaction cannot be so
strong to impede the reaction to take place. This important
role of both interactions with cations and anions involving CsF
salt in tert-butanol solvent has also been studied by molecular
dynamics methods, which supports the mechanism of an ion
pair reaction.7
The perception that molecules such as crown ethers, which
are able to make strong interaction with the cation,8,9 could
become more effective for solubilizing and activating MF salts
due to inclusion of groups able to interact with anions has led
to the design of new catalysts.10 Thus, polyethylene glycols
have been investigated and the pentaethylene glycol (Figure 1)
was found to be the most effective among them.11,12 New
structures combining calixarene, crown ether, and bulky
alcohols (BACCA, Figure 1) were designed and experimentally
tested.13−15 Hydroxylated crown ethers, named hydro-
crowns,16 were also designed, and computational methods
have predicted that the additional hydroxyl groups enhance the
Although theory and experiments have shown that the
combined functionalities in a single molecule with cation and
anion interaction leads to superior catalysis, these newly
designed structures involve more molecular complexity.10 An
alternative to this approach is to make the groups with cation
and anion interaction to be present in different molecules,
Received: September 15, 2020
https://dx.doi.org/10.1021/acs.joc.0c02229
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Figure 1. Evolution of structures able to interact with cations and/or anions to accelerate SN2 nucleophilic fluorination.
which would involve simpler structures. Thus, we have
hypothesized that the crown ether combined with a diol, 1,4-
benzenedimethanol (BDM, Figure 1), could also have a
catalytic effect in the fluorination with KF. However,
preliminary calculations have indicated that KF-18C6-BDM
complex can form a very stable dimer, which could inhibit the
catalysis. In order to make this dimer less stable, the hydrogens
in the carbons of the CH2OH groups were substituted by
methyl groups, leading to the bulky diol 1,4-bis(2-hydroxy-2-
propyl)benzene, which is named BDMb in this work. The
proposed activation mode is presented in Figure 1. In our view,
the SN2 transition state interacts with the bulk diol (BDMb
structure) and the fluoride ion remains in close contact with
the cation, which is complexed with the crown ether. Such
interaction should produce an important rate acceleration
effect.
In a previous work, we have investigated the bulky
monoalcohol (tert-butanol) making hydrogen bonding with
the fluoride ion in the KF(18-crown-6) complex and a catalytic
effect was theoretically predicted and experimentally ob-
served.21 In this work, our aim is to analyze if the double
hydrogen bonding as envisioned in Figure 1 could be even
more effective. Thus, we have performed a detailed theoretical
calculation of the model reaction of potassium fluoride with
ethyl bromide catalyzed by crown ether combined with the
bulk diol BDMb. Further, to evaluate the important role of the
position of the hydroxyl groups to promote the catalysis,
another diol with close hydroxyl groups, 2,2-dimethyl-1,3-
propanediol or neopentyl glycol (named PDIOL), was also
investigated. To confirm the theoretical predictions, some
selected experiments were also carried out. The reaction is
summarized in Scheme 1.
Scheme 1. Reaction Investigated in This Work
The role of hydrogen bonds involving the fluoride ion is not
limited to accelerate the SN2 reaction. Early experiments by
Landini and co-workers involving F−(H2O)n clusters and
tetrabutylammonium as counter ion in apolar solvent showed
that more hydrogen bonds lead to more selectivity of the SN2
reaction versus E2.22,23 Theoretical calculations involving
catalysis of fluorination by diol18,19 and tetraol24 have
predicted this trend. Kim et al. have also reported that tert-
amyl alcohol medium promotes selective fluorination of alkyl
halides with tetrabutylammonium fluoride.25 More recently,
Gouverneur and co-workers reported a detailed investigation
of the effect of stoichiometric diverse bulky alcohols26 and
ureas27 with specific solvation to the fluoride ion in acetonitrile
solvent. The same trend of SN2 selectivity promoted by
hydrogen bonding was observed. Thus, the present study also
evaluates the selectivity of SN2 product in the catalysis by 18-
crown-6 combined with bulky diols.
RESULTS AND DISCUSSION
In the phase-transfer-catalyzed fluorination of alkyl halide (or
mesylate) with KF salt, it is important to consider two steps:
■
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the solubilization of the salt, formation of the KF(cat)
complex, and the activation step involving the KF(cat)
complex in the transition state. In order to have insights in
the interactions involved, we have first analyzed the formation
of the complexes involving KF, crown ether, and the bulky
diols BDMb and PDIOL. In the next step, the activation
process was analyzed and in the third step, the free energy
profile.
substantial value. In the case of only KF + 18-crown-6, the
interaction energy reported is only 41.7 kcal mol−1. Thus, the
addition of BDMb diol should be able to produce a substantial
increase in the solubilization of KF salt. In the same way, the
PDIOL molecule has also high interaction energy with the
fluoride ion and the KF-18C6-PDIOL complex is stable by
78.3 kcal mol−1, as shown in Figure 2. There are two hydrogen
bonds between hydroxyls from PDIOL and the fluoride ion,
and the oxygens from PDIOL also interact with the potassium
ion. Thus, both complexes are very stable.
The complexes involving KF, 18-crown-6 and bulky diols are
presented in Figure 2. In the case of the complex with BDMb,
The second step is the activation, involving the reaction with
ethyl bromide via the SN2 transition state. It is worth to analyze
the intrinsic reactivity, without the solvent effect. In this
situation, very high difference can be noted for the complexes.
The energy barrier for the KF-18C6-BDMb and EtBr reaction
model via TS1-18C6-BDMb is 4.0 kcal mol−1, whereas it
becomes 21.3 kcal mol−1 in the case of TS1-18C6-PDIOL. For
comparison, the ΔE‡ barrier (Table S1, Supporting Informa-
tion) for the KF-18C6 + EtBr reaction is 3.7 kcal mol−1. With
the addition of tert-butanol as alcohol, the barrier becomes
12.7 kcal mol−1.21 Thus, the energy barrier via the KF-18C6-
BDMb complex is as low as the energy barrier for the reaction
via the KF-18C6 complex. These differences can be attributed
to how the diols interact with the transition state. The BDMb
species interact with both the incoming fluoride ion and the
leaving bromide ion. Thus, there is an additional hydrogen
bonding with a highly charged group (the leaving Br). To
provide more support for the role of the second hydroxyl,
another SN2 transition state involving BDMb, named TS1b-
18C6-BDMb and without this second hydrogen bond, was
located (Figure 2). In this case, the ΔE‡ barrier becomes 10.9
kcal mol−1, close to the tert-butanol barrier. In the case of
PDIOL, its strong interaction with the fluoride ion in the KF-
18C6-PDIOL complex is substantially decreased in the TS1-
18C6-PDIOL structure because part of the charge in the
fluoride ion is transferred to the leaving Br. As a consequence,
a high barrier is induced. Thus, this simple analysis indicated
that the diol with more distant hydroxyls (BDMb) able to
interact with the entering and leaving groups should be more
effective. Nevertheless, the solvent effect, entropy, and
solubility need be taken into account for a reliable prediction
on the ability of these alcohols to accelerate the SN2 reaction.
Finally, the E2 mechanism was also investigated and the
respective transition state, TS2-18C6-BDMb, has a high ΔE‡
barrier of 16.5 kcal mol−1. This result indicates an important
selectivity induced by the BDMb toward the SN2 mechanism
because the barrier for E2 catalyzed by 18-crown-6 only is 8.1
kcal mol−1.21
Figure 2. Complexes and transition states involving KF, 18-crown-6,
and the diols BDMb and PDIOL. The values of ΔE correspond to the
formation of the complexes from the separated species (KF, 18-
crown-6, and the diol). The activation barriers (ΔE‡) correspond to
SN2 and E2 transition states from the KF-18C6-diol + EtBr taken as
reference. Energies from LPNO-CEPA calculations. Atoms: oxygen
(red), carbon (gray), fluorine (light blue), bromine (wine), and
potassium (purple).
Formation of Aggregates. In the theoretical prediction
of catalytic processes, it is important to evaluate what species
are present in the solution phase. The formation of stable
aggregates can produce an increase in the observed free energy
barrier and eliminate any possible catalysis. Thus, we have
evaluated the formation of aggregates of KF-18C6 with two
BDMb molecules and also the possibility of the dimerization of
the KF-18C6-BDMb species. In this investigation, the
structures presented in Figure 3 were obtained. The KF-
18C6-BDMb2 complex is formed by the addition of one more
BDMb molecule to the KF-18C6-BDMb complex. The
fluoride ion makes two hydrogen bonds, and there is an
additional hydrogen bond between the hydroxyls from BDMb.
The addition of the second BDMb molecule has ΔE = −27.7
kcal mol−1. The other aggregate, (KF-18C6-BDMb)2, is the
the fluoride ion interacts with both the potassium ion and with
one hydroxyl of the BDMb. The second hydroxyl from BDMb
also makes a hydrogen bond with one oxygen from 18-crown-
6. The structure also suggests some cation−π interaction
between the K+ and the aromatic ring from BDMb. The total
interaction energy in this complex from KF (gas phase) + 18-
crown-6 + BDMb reference state is 72.5 kcal mol−1, a very
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even eliminate any catalytic effect. Thus, the free energy of
these species was also analyzed and included in the free energy
profile. The addition of a second molecule of BDMb, forming
the KF-18C6-BDMb2 species leads to higher stability, and the
free energy decrease to 0.9 kcal mol−1. In the case of the
dimerization of the KF-18C6-BDMb, forming the (KF-18C6-
BDMb)2 species, the free energy becomes 1.7 kcal mol−1,
taking into account the stoichiometry of the process. Thus,
based on these results, the formation of these complexes
should not decrease the predicted catalysis in acetonitrile.
However, in a less polar solvent, these complexes should
become more stable and have negative free energy, which
could result in inhibition of catalysis. Any theoretical
investigation of this kind of catalysis must consider the
possible formation of aggregates. Otherwise, reliable predic-
tions cannot be done.
Figure 3. Higher aggregates that can be formed involving KF-18C6
and BDMb.
dimerization of the KF-18C6-BDMb complex, and the
corresponding ΔE for dimerization is −38.9 kcal mol−1.
Thus, both aggregates have a strong interaction energy and
could be important in inhibition of the catalysis. Thus, these
species were considered in the calculation of the free energy
profile of the reaction.
The calculations predict that the E2 transition state (TS2-
18C6-BDMb in Figure 2) is much less favorable than the SN2
one, with a free energy barrier 5 kcal mol−1 higher than the SN2
pathway (Table S1). Based on this data, only a trace of the E2
product should be formed by this catalysis.
Free Energy Profile. In order to predict quantitatively any
catalytic effect, it is needed to generate the free energy profile
for each step, including the solubilization of the KF salt. The
catalysis by 18-crown-6 and BDMb is presented in Figure 4.
For completeness, the previously reported catalysis by 18-
crown-6, studied in the same level of theory, was also included.
The solubilization of the solid KF salt by 18-crown-6 in
acetonitrile has a free energy of 8.8 kcal mol−1, and considering
the activation step, the final ΔG‡ barrier is 32.0 kcal mol−1.
This value is compatible with the experimental kinetics which
requires long reaction time and refluxing conditions. With the
addition of BDMb to the medium, forming the KF-18C6-
BDMb complex, the solubilization increases and the free
energy decreases to 3.8 kcal mol−1. The activation step involves
the TS1-18C6-BDMb transition state with a ΔG‡ barrier of
24.3 kcal mol−1, a substantial decrease by 7.7 kcal mol−1 from
the crown ether catalysis. Thus, in the absence of another
equilibrium able to stabilize the pre-reactive complex, a very
meaningful catalytic effect is predicted by the combination of
crown ether and BDMb. The formation of aggregates
presented in Figure 3 could make the reaction slower or
Considering the free energy profile, the rate law is predicted
to be given by:
d[RBr]
dt
= −k[BDMb][18C6][RBr]
(1)
with the rate constant k related to ΔG‡ = 24.3 kcal mol−1. The
derivation is presented in the Supporting Information.
The theoretical free energy profile in Figure 4 shows that the
present combination of BDMb with 18-crown-6 leads to a true
catalytic system, with release of the diol and of the crown
ether. The formed KBr-18C6-BDMb complex (and RF
product) has a relative free energy of −7.4 kcal mol−1. The
release of the BDMb, forming KBr-18C6, is favorable, and its
free energy is −8.5 kcal mol−1. This result shows that BDMb
does not form a favorable complex with KBr-18C6. A different
behavior occurs for KF-18C6 because complexation with
BDMb decreases the free energy from 8.8 to 3.8 kcal mol−1.
Further, the KBr-18C6 complex has relative free energy of
−8.5 kcal/mol and when the dissociation of this complex takes
place, forming solid KBr and free 18-crown-6, the free energy
Figure 4. Free energy profile for the KF(s) + 18-crown-6 + BDMb reaction in acetonitrile solvent. Calculations at LPNO-CEPA1/ma-def2-
TZVPP//PBE/ma-def2-SVP level of theory. Solvent effect calculated by the SMD model.
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Figure 5. Free energy profile for the KF(s) + 18-crown-6 + PDIOL reaction in acetonitrile solvent. Calculations at the LPNO-CEPA1/ma-def2-
TZVPP//PBE/ma-def2-SVP level of theory. Solvent effect calculated by the SMD model.
a
Table 1. Experiments of Fluorination Reactions
entry
KF (mmol)
bulky alcohol
bulky alcohol (mmol)
yield (%) of 2
yield (%) of 3
ref
1
2
3
4
5
2
2
2
2
2
4.7
13.5
22
46
17
trace
3.5
trace
3
21
21
this work
this work
this work
tert-butanol
BDMb
BDMb
1
1
3
1
BDMbp
trace
a
Experiments using 1 mmol of (3-bromopropoxy)benzene, 1 mmol of 18-crown-6, and 4 mL of the acetonitrile solvent. The reaction mixture was
heated to reflux (82 °C) during 24 h.
becomes −10.0 kcal mol−1, which is 1.5 kcal mol−1 below KBr-
18C6. Thus, both the 18C6 and BDMb are free for a new
catalytic cycle. Therefore, it is a true catalysis. Based on the
kinetic law, we could use sub-stoichiometric concentration of
both BDMb and 18C6. However, in the experimental part, we
have used stoichiometric quantities of the BDMb and 18-
crown-6 to produce a faster kinetics. In our view, more design
of the diol could lead to a more enhanced rate acceleration
effect and more efficient catalysis.
formation of two hydrogen bonds with the fluoride ion makes
the solubilization more favorable. Such an observation also
suggests that a tetraol with distant pairs of hydroxyls like
NPTROL could produce a further enhanced catalytic effect.24
Another interesting observation is that Gouverneur and co-
workers have also reported that the diol neopentyl glycol has
produced substantially less reactivity in fluorination with
tetrabutylammonium fluoride than bulky monoalcohols, in
line with the present report.26
The free energy profile for the reaction catalyzed by another
diol (PDIOL) was also calculated and is presented in Figure 5.
The strong interaction of this diol with KF-18C6 leads to an
even more stable complex, KF-18C6-PDIOL, with a free
energy of only 0.8 kcal mol−1. However, as expected from
previous analysis, the activation step is very unfavorable and
the ΔG‡ considering the solubilized KF-18C6-PDIOL complex
is 29.3 kcal mol−1. For comparison, in the case of BDMb, this
same barrier is 20.5 kcal mol−1. Nevertheless, because the
PDIOL leads to better solubilization, the overall ΔG‡
considering the solid KF is 30.1 kcal mol−1. Thus, the
calculation predicts that even this diol has a small catalytic
effect and the decrease in the ΔG‡ in relation to the 18-crown-
6 catalysis is predicted to be 1.9 kcal mol−1.
EXPERIMENTAL RESULTS
■
Based on the theoretical studies, a structure like BDMb should be
effective to provide the catalysis, whereas PDIOL should not. Thus,
we have investigated experimentally the reaction in Scheme 1 using
BDMb and BDMbp as diols. The reaction was carried out in
acetonitrile solvent, under reflux (82 °C) and using 2 mmol of KF, 1
mmol of 18-crown-6, and 1 to 3 mmol of the diols. The results are
presented in Table 1, and we have included the results of a previous
study using tert-butanol as bulky alcohol for comparison.21
In the reaction catalyzed by 18-crown-6, the fluorination yield is
only 4.7% after 24 h (entry 1). With the use of 1 mmol of tert-butanol
in our previous report (entry 2), the yield increased to 13.5%. In the
case of the BDMb diol used in this work, the yield was 22% (entry 3),
almost twice the yield with tert-butanol using 1 mmol. With the
increase of the concentration of BDMb (use of 3 mmol), the yield
reached 46%, in line with eq 1 that predicts linear dependence of the
kinetics with the concentration of BDMb. In the last experiment
The present theoretical results suggest that diols similar to
BDMb, with distant hydroxyls, should be more effective for
catalysis than diols with close hydroxyls. On the other hand,
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(entry 5), using the BDMbp diol, the yield was smaller than that
observed for BDMb. Thus, the present experiments point out that a
combination of 18-crown-6 with the BDMb diol produces a
substantial increase of the phase-transfer-catalyzed fluorination of a
primary alkyl bromide in relation to the use of 18-crown-6 only.
Furthermore, the BDMb is more efficient than tert-butanol to
accelerate the reaction.
Another important aspect of this study is the high selectivity
observed for crown ether-BDMb catalysis. In entry 4, the fluorination
yield was 46%, while the E2 yield was only 3%. The SN2/E2 ratio is
15, a substantially better value than that reported for complexes of
bulky alcohols with tetrabutylammonium fluoride,26 which are in the
range from 1 to 4.
reaction time. Thus, we think that a comparison using 0.25 mol L−1
and a shorter reaction time is more adequate because it avoids
aggregation effects and possible secondary reactions that can occur in
a longer reaction time.
In the case of crown ether and BDMb catalysis, entry 3 leads to an
experimental free energy barrier of 28.1 kcal mol−1, whereas higher
concentration of BDMb (entry 4) leads to a slightly higher value of
28.2 kcal mol−1. The predicted theoretical ΔG‡ is 24.3 kcal mol−1, a
difference of 3.8 kcal mol−1. This is a reasonable agreement, although
the theoretical accuracy is not so good as that obtained for tert-
butanol catalysis. Thus, the rate acceleration effect predicted by
theory due to addition of BDMb to crown ether catalysis is
experimentally verified. However, the observed effect is smaller than
predicted by theory. Another bulk diol (BDMbp) was also
experimentally tested (entry 5) and the estimated ΔG‡ was 28.4
kcal mol−1, slightly higher than the BDMb catalysis. This result
indicates that there is no advantage of using this more complex
molecule.
Comparison between Theory and Experiment. The exper-
imental data can be used for estimating ΔG‡ and for making a
comparison with theoretical values. Thus, we need to consider a
kinetic model. Based on the calculation of the free energy profile, we
can consider the rate law for alkyl bromide decay as:
A question that arises is what is the reason for the error in the
theoretical calculations to be higher for the BDMb catalysis than for
tert-butanol? In part, the error in the theory is due to the temperature
used in the calculations (25 °C) while the experiments were done at
82 °C. A substantial −TΔS term is expected because the transition
state merges three species to form the transition sate. As a rough
estimate, considering ΔS = −50 cal K−1 mol−1, the variation of the
−TΔS term is (−T2ΔS + T1ΔS) = −ΔTΔS. When going from 25 to
82 °C, ΔT = 57 K and we can calculate that −ΔTΔS = 2.9 kcal mol−1,
which increases ΔG‡ to 27.2 kcal mol−1 at 82 °C, very close to the
experimental value of 28.1 kcal mol−1. On the other hand, such an
effect would also increase the error in barrier predicted for the tert-
butanol catalysis (see ref 21. In our opinion, it would be desirable to
use more reliable theoretical methods, including explicit solvent
molecules and better treatment of low vibrational frequencies to make
more accurate predictions. Nevertheless, it is important to say that the
present theoretical approach was able to correctly predict the catalytic
effect and has guided the experiments toward the proof of this kind of
catalysis. Further optimization of experimental conditions and use of
another diol structure could lead to more effective catalysis and even
stereochemical control via chiral diols.
d[RBr]
= −(kc + kcd[BDMb])[18C6][RBr]
(2)
dt
where kc is the rate constant for crown ether catalysis and kcd is the
rate constant for crown ether and diol catalysis. Based on the data in
Table 1, we have considered the concentration of alkyl bromide and
crown ether as 0.25 mol L−1, while the diol is 0.25 mol L−1 (1 mmol)
and 0.75 mol L−1 (3 mmol). The reaction rate for alkyl bromide decay
can be rewritten as:
d[RBr]
dt
= −keff[RBr]
(3)
where keff is the pseudo-first order rate constant given by:
keff = (kc + kcd[BDMb])[18C6]
(4)
Considering the reaction time and the yield (conversion), we can
estimate keff by the first-order decay:
[RBr]t = [RBr]0. e−k
eff·t
(5)
Thus, the 4.7% conversion in Table 1 (entry 1) leads to keff = 5.6 ×
10−7 s−1 and because [18C6] = 0.25 mol L−1, we can estimate that kc
= 2.2 × 10−6 L mol−1 s−1. Once the rate constant is known, the ΔG‡
can be determined from the transition state theory and the
temperature of the reaction. This procedure was applied for entries
1 to 5 in Table 1 to estimate the rate constants and the respective
ΔG‡, which are presented in Table 2.
CONCLUSIONS
■
The combined effect of 18-crown-6 and bulky diol (BDMb)
for phase-transfer-catalyzed fluorination of an alkyl bromide
using potassium fluoride reagent was investigated by
theoretical methods and experiments. The calculations indicate
the BDMb works by stabilizing the SN2 transition state via two
hydrogen bonds to the incoming and leaving groups. Thus, a
catalytic effect was predicted for this combination, which was
confirmed by the experiments. Based on the estimated
experimental kinetic data, using BDMb at 1 mol L−1
concentration combined with crown ether leads to rate
acceleration by 18-fold in relation to crown ether catalysis
only. In addition, the catalyzed reaction is highly selective,
producing a minimal E2 product. Therefore, this study
presents an improved fluorination method using the KF
reagent, 18-crown-6, and the bulky diol BDMb.
Table 2. Estimated Experimental Kinetic Parameters Based
on a Simple Analysis of the experiments
a
entry
keff (s−1
5.6 × 10−7
keff (s−1
)
kc (L mol−1 s−1
2.2 × 10−6
)
ΔG‡ (kcal mol−1
)
b
1
30.1
entry
)
kcd (L2 mol−2 s−1
)
ΔG‡ (kcal mol−1
)
b
2
3
4
5
1.7 × 10−6
2.9 × 10−6
7.1 × 10−6
2.2 × 10−6
1.8 × 10−5
3.7 × 10−5
3.5 × 10−5
2.6 × 10−5
28.6
28.1
28.2
28.4
a
Values determined based on the data from Table 1 and the kinetic
equations 2−5. Taken from ref 21.
b
EXPERIMENTAL SECTION
■
The free energy barrier for crown ether catalysis was reported in
our previous study and the experimental estimate is 30.1 kcal mol−1,
close to the theoretical value of 32.0 kcal mol−1. In the case of the
addition of tert-butanol, both theory and experiments are also in very
good agreement with the theoretical barrier predicted to be 28.4 kcal
mol−1, whereas the experimental value is 28.6 kcal mol−1.21 It is worth
to say that another two experiments with tert-butanol led to a slightly
lower experimental barrier of 28.3 kcal mol−1. However, those
experiments have involved more concentrated solutions and longer
NMR Analysis. Proton (1H) and carbon (13C{1H}) NMR spectra
were recorded on a Bruker 500 MHz in CDCl3 spectrometer at the
Federal University of Juiz de Fora. Chemical shifts (δ) are reported in
parts per million with reference to residual CHCl3 (1H, 7.26; 13C,
77.00).
General Procedure. (3-Bromopropoxy)benzene (1.00 mmol,
158.00 μL, purchased from Sigma-Aldrich) was added to a solution of
potassium fluoride (2.00 mmol), 18-crown-6 (1.00 mmol), 1,4-bis(2-
hydroxyisopropyl)benzene or 1,4-bis(diphenylhydroxymethyl)-
F
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benzene (1.00 or 3.00 mmol) in acetonitrile (directly from the
bottle), and the reaction was refluxed in an oil bath for 24 h. The
solvent of the reaction was concentrated under reduced pressure, and
purification of the resulting residue by flash chromatography on silica
gel (EtOAc/heptane 05:95) (to remove essentially the crown ether)
afforded a pale yellow oil. In this stage, the oil obtained was analyzed
by NMR. The yields were calculated by integration of the spectra of
1H NMR and are showed in Table 1.
E(CEPA/ma − def2 − TZVPP)
≅ E(CEPA/ma − def2 − SVP) + E(MP2/ma − def2
− TZVPP) − E(MP2/ma − def2 − SVP)
(6)
.
The MP2 calculations were done with the resolution of identity
approximation, and all the electrons were correlated in the CEPA and
MP2 calculations. The LPNO-CEPA energies were considered the
best level of theory, and the respective energies were used for
obtaining the free energy profile.
Spectroscopy Data.
The solvent effect was included through single-point energy
calculations using the SMD method.40 The X3LYP functional41 with
the 6-31(+)G(d) basis set was used for the electronic density in the
SMD computations. Thus, the present calculations of the free energy
are a composite method and the free energy for each species in the
solution phase (acetonitrile solvent) is given by:
Gsol = Eel + Gvrt + ΔGsolv + 1.89 kcal mol−1
(3-Bromopropoxy)benzene. Colorless liquid. 1H NMR (CDCl3, 500
MHz): δ 7.39 (2H, H-3′, J 7.3 Hz, t), 7.06 (1H, H-4′, J 7.3 Hz, t),
2.39 (2H, H-2, J 6.1 Hz, quint), 7.01 (2H, H-2′, J 8.5 Hz, d), 4.17
(2H, H-1, J 6.0 Hz, t), 3.68 (2H, H-3, J 6.4 Hz, t). 13C{1H} NMR
(CDCl3, 125 MHz): δ 158.8 (C-1′), 129.6 (C-3′), 121.0 (C-4′),
114.6 (C-2′), 65.3 (C-1), 32.5 (C-3), 30.2 (C-2).
(7)
where Eel is the electronic energy calculated by the LPNO-CEPA
method, Gvrt is the vibrational, rotational, and translational
contribution to the free energy (1 atm), ΔGsolv is the solvation free
energy, and the 1.89 kcal mol−1 is the correction from 1 atm to the 1
mol L−1 standard state. Thus, the final solution phase free energy, Gsol,
corresponds to the 1 mol L−1 standard state. In some structures, there
are additional imaginary modes due to almost free rotation of methyl
groups and the formation of supramolecular complexes. We have
corrected the vibrational partition function to make equal number of
degrees of freedom for each side in the reaction equation.
Because the KF salt is a solid, experimental thermodynamics data
must be included for correct description of its solubilization. In our
approach, we have considered the free energy for sublimation of the
KF salt taken from NIST:
(3-Fluoropropoxy)benzene (Ref 28. Colorless oil. 1H NMR
(CDCl3, 500 MHz): δ 7.39 (2H, H-3′, J 7.3 Hz, t). 7.06 (H-4′,
1H, J 7.3 Hz, t), 7.01 (2H, H-2′, J 8.5 Hz, d), 4.65 (2H, H-3, J 47.0
Hz, J 6.0 Hz, dt), 4.10 (2H, H-1, J 6.0 Hz, t), 2.16 (2H, H-2, dquint, J
25.9 Hz, J 6.0 Hz, dquint). 13C{1H} NMR (CDCl3, 125 MHz): δ
158.8 (C-1′), 129.6 (C-3′), 121.0 (C-4′), 114.6 (C-2′), 80.8 (C-3, J
164.0 Hz, d), 63.5 (C-1), 30.4 (C-2′, J 20.0 Hz, d).
KF (s) → KF (g) ΔG1
= 48.3 kcal. mol−1 (1 mol/L standard state)
and calculated the process:
KF (g) + 18C6 (sol)
→ KF‐18C6 (sol) ΔG2
= −39.5 kcal. mol−1
1
(Allyloxy)benzene (Ref 29. Colorless solid. H NMR (CDCl3, 500
MHz): δ 7.39 (2H, H-3′, J 7.3 Hz, t), 7.06 (1H, H-4′, J 7.3 Hz, t),
7.01 (2H, H-2′, J 8.5 Hz, d), 6.01 (1H, H-2, J 17.0 Hz, J 10.5 Hz, J 5.3
Hz, dquint), 5.47 (1H, H-3a, Jtrans 17.0 Hz, Jgem 1.5 Hz, dd), 5.30 (1H,
H-3, Jcis 10.5 Hz, Jgem 1.5 Hz, dd), 4.57 (2H, H-1, J 5.3 Hz, d).
13C{1H} NMR (CDCl3, 125 MHz): δ 158.8 (C-1′), 133.5 (C-2),
129.6 (C-3′), 121.0 (C-4′), 114.6 (C-2′), 117.6 (C-3), 68.8 (C-1).
Theoretical Methods. The stationary points on the potential
energy surface for the model reaction of KF with ethyl bromide
catalyzed by 18-crown-6 and the diols BDMb and PDIOL were
obtained by geometry optimization using the PBE functional.30 For
these optimizations, the def2-SVP basis set31 was used for carbon,
hydrogen, and potassium, and the ma-def2-SVP basis set32 was used
for oxygen, fluorine, and bromine. Harmonic frequency calculations
were done for the optimized structures to obtain the vibrational,
rotational, and translations contributions to the free energy. Aimed to
obtain more accurate electronic energies, single point energy
calculations were done at M06-2X,33 MP2, and LPNO-CEPA/
where (s) means solid, (g) means gas, and (sol) means solution phase.
Thus, combining the two equations, we have the solubilization free
energy of KF by the 18C6:
KF (s) + 18C6 (sol) → KF‐18C6 (sol) ΔG3 = ΔG1 + ΔG2
= 8.8 kcal. mol−1
All the PBE, M06-2X, MP2, and LPNO-CEPA calculations were
done with the ORCA 3 program,42,43 whereas the SMD calculations
were done with the GAMESS program.44,45
In the calculations of ΔG‡ in the liquid phase, we have used the
separable equilibrium solvation approach,46 which is based on the
rigorous formulation of the transition state theory. Empirical
translational entropy correction, which does not have any theoretical
support, was not included.
ASSOCIATED CONTENT
■
1
34−37 levels of theory. The M06-2X and MP2 calculations were done
with the def2-TZVPP basis set31 for carbon, hydrogen, and potassium,
and the ma-def2-TZVPP basis set32 for oxygen, fluorine, and bromine.
The LPNO-CEPA/1 calculations were done with the smaller ma-
def2-SVP basis set (as defined above), and the estimation of the
LPNO-CEPA energies with the higher ma-def2-TZVPP basis set was
done by the additivity approximation of the correlation energy:38,39
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02229.
Coordinates of the optimized structures and table of the
calculations (PDF)
G
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glycols as highly efficient mutifunctional promoters for nucleophilic-
substitution reactions. Chem. − Eur. J. 2012, 18, 3918−3924.
(12) Lee, J. W.; Yan, H.; Jang, H. B.; Kim, H. K.; Park, S.-W.; Lee, S.;
Chi, D. Y.; Song, C. E. Bis-terminal hydroxy polyethers as all-purpose,
multifunctional organic promoters: A mechanistic investigation and
applications. Angew. Chem., Int. Ed. 2009, 48, 7683−7686.
(13) Han, H. J.; Lee, S.-S.; Kang, S. M.; Kim, Y.; Park, C.; Yoo, S.;
Kim, C. H.; Oh, Y.-H.; Lee, S.; Kim, D. W. The effects of structural
modifications of bis-tert-alcohol-functionalized crown-calix[4]arenes
as nucleophilic fluorination promotors and relations with computa-
tional predictions. Eur. J. Org. Chem. 2020, 2020, 728−735.
(14) Kang, S. M.; Kim, C. H.; Lee, K. C.; Kim, D. W. Bis-triethylene
glycolic crown-5-calix[4]arene: A promoter of nucleophilic fluorina-
tion using potassium fluoride. Org. Lett. 2019, 21, 3062−3066.
(15) Jadhav, V. H.; Choi, W.; Lee, S.-S.; Lee, S.; Kim, D. W. Bis-tert-
alcohol-functionalized crown-6-calix[4]arene: An organic promoter
for nucleophilic fluorination. Chem. − Eur. J. 2016, 22, 4515−4520.
(16) Carvalho, N. F.; Pliego, J. R., Jr. Theoretical design and
calculation of a crown ether phase-transfer-catalyst scaffold for
nucleophilic fluorination merging two catalytic concepts. J. Org.
Chem. 2016, 81, 8455−8463.
AUTHOR INFORMATION
Corresponding Author
Josefredo R. Pliego, Jr − Departamento de Ciências Naturais,
Universidade Federal de Säo Joäo del-Rei, Säo Joäo del-Rei
36301-160, MG, Brazil; orcid.org/0000-0002-2944-
5332; Email: pliego@ufsj.edu.br
■
Authors
Samuel L. Silva − Departamento de Ciências Naturais,
Universidade Federal de Säo Joäo del-Rei, Säo Joäo del-Rei
36301-160, MG, Brazil
Marcelo S. Valle − Departamento de Ciências Naturais,
Universidade Federal de Säo Joäo del-Rei, Säo Joäo del-Rei
36301-160, MG, Brazil
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02229
Notes
The authors declare the following competing financial
interest(s): A patent application was filled.
(17) Dalessandro, E. V.; Pliego, J. R. Theoretical design of new
macrocycles for nucleophilic fluorination with KF: Thiourea-crown-
ether is predicted to overcome the [2.2.2]-cryptand. Mol. Syst. Des.
Eng. 2020, 1513.
ACKNOWLEDGMENTS
The authors thank the agencies CNPq, FAPEMIG, and
CAPES for support.
■
(18) Pliego, J. R. First solvation shell effects on ionic chemical
reactions: New insights for supramolecular catalysis. J. Phys. Chem. B
2009, 113, 505−510.
REFERENCES
■
́
(19) Pliego, J. R.; Pilo-Veloso, D. Chemoselective nucleophilic
(1) Lee, J.-W.; Oliveira, M. T.; Jang, H. B.; Lee, S.; Chi, D. Y.; Kim,
D. W.; Song, C. E. Hydrogen-bond promoted nucleophilic
fluorination: Concept, mechanism and applications in positron
emission tomography. Chem. Soc. Rev. 2016, 45, 4638−4650.
(2) Liang, S.; Hammond, G. B.; Xu, B. Hydrogen bonding:
Regulator for nucleophilic fluorination. Chem. − Eur. J. 2017, 23,
17850−17861.
(3) Kim, D. W.; Jeong; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen, J.
A.; Chi, D. Y. Facile nucleophilic fluorination reactions using tert-
alcohols as a reaction medium: Significantly enhanced reactivity of
alkali metal fluorides and improved selectivity. J. Org. Chem. 2008, 73,
957−962.
(4) Kim, D. W.; Ahn, D. S.; Oh, Y. H.; Lee, S.; Kil, H. S.; Oh, S. J.;
Lee, S. J.; Kim, J. S.; Ryu, J. S.; Moon, D. H.; et al. A new class of sn2
reactions catalyzed by protic solvents: Facile fluorination for isotopic
labeling of diagnostic molecules. J. Am. Chem. Soc. 2006, 128, 16394−
16397.
(5) Oh, Y. H.; Ahn, D. S.; Chung, S. Y.; Jeon, J. H.; Park, S. W.; Oh,
S. J.; Kim, D. W.; Kil, H. S.; Chi, D. Y.; Lee, S. Facile sn2 reaction in
protic solvent: Quantum chemical analysis. J. Phys. Chem. A 2007,
111, 10152−10161.
(6) Parker, A. J. Protic-dipolar aprotic solvent effects on rates of
bimolecular reactions. Chem. Rev. 1969, 69, 1.
(7) Pliego, J. R., Jr. Molecular dynamics and cluster-continuum
insights on bulk alcohols effects on SN2 reactions of potassium and
cesium fluorides with alkyl halides. J. Mol. Liq. 2017, 237, 157−163.
(8) Liotta, C. L.; Harris, H. P. Chemistry of naked anions. I.
Reactions of the 18-crown-6 complex of potassium fluoride with
organic substrates in aprotic organic solvents. J. Am. Chem. Soc. 1974,
96, 2250−2252.
(9) Pliego, J. R., Jr.; Riveros, J. M. New insights on reaction pathway
selectivity promoted by crown ether phase-transfer catalysis: Model
ab initio calculations of nucleophilic fluorination. J. Mol. Catal. A -
Chem. 2012, 363-364, 489−494.
fluorination induced by selective solvation of the sn2 transition state.
J. Phys. Chem. B 2007, 111, 1752−1758.
(20) Pliego, J. R. Mechanism of nucleophilic fluorination promoted
by bis-tert-alcohol-functionalized crown-6-calix[4]arene. Int. J.
Quantum Chem. 2018, 118, No. e25648.
(21) Silva, S. L.; Valle, M. S.; Pliego, J. R., Jr. Micro-solvation and
counter ion effects on ionic reactions: Activation of potassium
fluoride with 18-crown-6 and tert-butanol in aprotic solvents. J. Mol.
Liq. 2020, 319, 114211.
(22) Landini, D.; Maia, A.; Rampoldi, A. Dramatic effect of the
specific solvation on the reactivity of quaternary ammonium fluorides
and poly(hydrogen fluorides), (HF)n.cntdot.F-, in media of low
polarity. J. Org. Chem. 1989, 54, 328−332.
(23) Albanese, D.; Landini, D.; Penso, M. Hydrated tetrabutylam-
monium fluoride as a powerful nucleophilic fluorinating agent. J. Org.
Chem. 1998, 63, 9587−9589.
(24) Pliego, J. R., Jr. Chemical reactions inside structured nano-
environment: SN2vs. E2 reactions for the F‑ + CH3CH2Cl system.
Phys. Chem. Chem. Phys. 2011, 13, 779−782.
(25) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Facile
nucleophilic fluorination of primary alkyl halides using tetrabutylam-
monium fluoride in a tert-alcohol medium. Tetrahedron Lett. 2010, 51,
432−434.
(26) Engle, K. M.; Pfeifer, L.; Pidgeon, G. W.; Giuffredi, G. T.;
Thompson, A. L.; Paton, R. S.; Brown, J. M.; Gouverneur, V.
Coordination diversity in hydrogen-bonded homoleptic fluoride-
alcohol complexes modulates reactivity. Chem. Sci. 2015, 6, 5293−
5302.
(27) Pfeifer, L.; Engle, K. M.; Pidgeon, G. W.; Sparkes, H. A.;
Thompson, A. L.; Brown, J. M.; Gouverneur, V. Hydrogen-bonded
homoleptic fluoride−diarylurea complexes: Structure, reactivity, and
coordinating power. J. Am. Chem. Soc. 2016, 138, 13314−13325.
(28) Iwasaki, T.; Fukuoka, A.; Yokoyama, W.; Min, X.; Hisaki, I.;
Yang, T.; Ehara, M.; Kuniyasu, H.; Kambe, N. Nickel-catalyzed
coupling reaction of alkyl halides with aryl grignard reagents in the
presence of 1,3-butadiene: Mechanistic studies of four-component
coupling and competing cross-coupling reactions. Chem. Sci. 2018, 9,
2195−2211.
(10) Pliego, J. R. Potassium fluoride activation for the nucleophilic
fluorination reaction using 18-crown-6, [2.2.2]-cryptand, penta-
ethylene glycol and comparison with the new hydro-crown scaffold:
A theoretical analysis. Org. Biomol. Chem. 2018, 16, 3127−3137.
(11) Jadhav, V. H.; Jang, S. H.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.;
Kim, J.-Y.; Lee, S.; Lee, J. W.; Song, C. E.; Kim, D. W. Oligoethylene
H
https://dx.doi.org/10.1021/acs.joc.0c02229
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(29) Joo, S.-R.; Lim, I.-K.; Kim, S.-H. An alternative route for boron
phenoxide preparation from arylboronic acid and its application for
CO bond formation. Tetrahedron Lett. 2020, 61, 152197.
(30) Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized gradient
approximation made simple. Phys. Rev. Lett. 1996, 77, 3865−3868.
(31) Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence,
triple zeta valence and quadruple zeta valence quality for h to rn:
Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7,
3297−3305.
(32) Zheng, J.; Xu, X.; Truhlar, D. G. Minimally augmented
karlsruhe basis sets. Theor. Chem. Acc. 2011, 128, 295−305.
(33) Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals
for main group thermochemistry, thermochemical kinetics, non-
covalent interactions, excited states, and transition elements: Two
new functionals and systematic testing of four M06-class functionals
and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215−241.
(34) Kollmar, C.; Neese, F. The coupled electron pair approx-
imation: Variational formulation and spin adaptation. Mol. Phys. 2010,
108, 2449−2458.
(35) Neese, F.; Wennmohs, F.; Hansen, A. Efficient and accurate
local approximations to coupled-electron pair approaches: An attempt
to revive the pair natural orbital method. J. Chem. Phys. 2009, 130,
114108.
(36) Neese, F.; Hansen, A.; Wennmohs, F.; Grimme, S. Accurate
theoretical chemistry with coupled pair models. Acc. Chem. Res. 2009,
42, 641−648.
(37) Wennmohs, F.; Neese, F. A comparative study of single
reference correlation methods of the coupled-pair type. Chem. Phys.
2008, 343, 217−230.
(38) Curtiss, L. A.; Raghavachari, K.; Trucks, G. W.; Pople, J. A.
Gaussian-2 theory for molecular energies of first- and second-row
compounds. J. Chem. Phys. 1991, 94, 7221.
(39) Nobes, R. H.; Bouma, W. J.; Radom, L. The additivity of
polarization function and electron correlation effects in ab initio
molecular-orbital calculations. Chem. Phys. Lett. 1982, 89, 497.
(40) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal
solvation model based on solute electron density and on a continuum
model of the solvent defined by the bulk dielectric constant and
atomic surface tensions. J. Phys. Chem. B 2009, 113, 6378−6396.
(41) Xu, X.; Zhang, Q.; Muller, R. P.; Goddard, W. A., III An
extended hybrid density functional (x3lyp) with improved descrip-
tions of nonbond interactions and thermodynamic properties of
molecular systems. J. Chem. Phys. 2005, 122, 014105−014114.
(42) Neese, F.; Wennmohs, F.; Becker, U.; Riplinger, C. The orca
quantum chemistry program package. J. Chem. Phys. 2020, 152,
224108.
(43) Neese, F. The ORCA program system. WIREs Comput. Mol. Sci.
2012, 2, 73−78.
(44) Barca, G. M. J.; Bertoni, C.; Carrington, L.; Datta, D.; de Silva,
N.; Deustua, J. E.; Fedorov, D. G.; Gour, J. R.; Gunina, A. O.; Guidez,
E.; et al. Recent developments in the general atomic and molecular
electronic structure system. J. Chem. Phys. 2020, 152, 154102.
(45) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K.
A.; Su, S.; et al. General atomic and molecular electronic structure
system. J. Comput. Chem. 1993, 14, 1347−1363.
(46) Chuang, Y. Y.; Cramer, C. J.; Truhlar, D. G. The interface of
electronic structure and dynamics for reactions in solution. Int. J.
Quant. Chem. 1998, 70, 887−896.
I
https://dx.doi.org/10.1021/acs.joc.0c02229
J. Org. Chem. XXXX, XXX, XXX−XXX