Inter-and intra-molecular organocatalysis of sn2 fluorination by crown ether: Kinetics and quantum chemical analysis

Article abstract of DOI:10.3390/molecules26102947

We present the intra-and inter-molecular organocatalysis of S_N2 fluorination using CsF by crown ether to estimate the efficacy of the promoter and to elucidate the reaction mechanism. The yields of intramolecular S_N2 fluorination of

Full text of DOI:10.3390/molecules26102947

molecules
Article
Inter- and Intra-Molecular Organocatalysis of SN2 Fluorination
by Crown Ether: Kinetics and Quantum Chemical Analysis
Young-Ho Oh 1,†, Wonhyuck Yun 2,†, Chul-Hee Kim 2, Sung-Woo Jang 1, Sung-Sik Lee 1, Sungyul Lee 1,* and
Dong-Wook Kim 2,
*
1
2
Department of Applied Chemistry, Kyung Hee University, Duckyoung-daero 1732,
Yongin City 446-701, Korea; chem_yhoh@daum.net (Y.-H.O.); dughtndk23@naver.com (S.-W.J.);
int_shik@hotmail.com (S.-S.L.)
Department of Chemistry, Inha University, 100 Inha-ro, Nam-gu, Incheon 402-751, Korea;
wh0608777@gmail.com (W.Y.); cg7633@naver.com (C.-H.K.)
*
Correspondence: sylee@khu.ac.kr (S.L.); kimdw@inha.ac.kr (D.-W.K.); Tel.: +82-31-201-2698 (S.L.);
+82-32-860-7679 (D.-W.K.); Fax: +82-31-201-2340 (S.L.); +82-32-867-5604 (D.-W.K.)
These authors contributed equally to this work.
†
Abstract: We present the intra- and inter-molecular organocatalysis of SN2 fluorination using CsF by
crown ether to estimate the efficacy of the promoter and to elucidate the reaction mechanism. The
yields of intramolecular SN2 fluorination of the veratrole substrates are measured to be very small
(<1% in 12 h) in the absence of crown ether promoters, whereas the SN2 fluorination of the substrate
possessing a crown ether unit proceeds to near completion (~99%) in 12 h. We also studied the
efficacy of intermolecular rate acceleration by an independent promoter 18-crown-6 for comparison.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
We find that the fluorinating yield of a veratrole substrate (leaving group =
−
OMs) in the presence
ꢀꢁꢂꢃꢄꢅꢆ
of 18-crown-6 follows the almost identical kinetic course as that of intramolecular SN2 fluorination,
indicating the mechanistic similarity of intra- and inter-molecular organocatalysis of the crown ether
for SN2 fluorination. The calculated relative Gibbs free energies of activation for these reactions,
in which the crown ether units act as Lewis base promoters for SN2 fluorination, are in excellent
agreement with the experimentally measured yields of fluorination. The role of the metal salt CsF is
Citation: Oh, Y.-H.; Yun, W.; Kim,
C.-H.; Jang, S.-W.; Lee, S.-S.; Lee, S.;
Kim, D.-W. Inter- and Intra-Molecular
Organocatalysis of SN2 Fluorination
by Crown Ether: Kinetics and
−
briefly discussed in terms of whether it reacts as a contact ion pair or as a “free” nucleophile F .
Quantum Chemical Analysis.
Molecules 2021, 26, 2947. https://
doi.org/10.3390/molecules26102947
Keywords: organocatalysis; SN2 fluorination; crown ether; quantum chemistry
Academic Editor: Seung Seo Lee
Received: 19 April 2021
Accepted: 12 May 2021
Published: 15 May 2021
1. Introduction
SN2 reactions [1–13] are such fundamental chemical transformations that have been
studied for so long that the mechanism of this important and useful process is usually con-
sidered to be perfectly understood. There have been, however, some studies [4,5,8,13–15]
proposing that the mechanism of SN2 reactions may not be so unambiguous. Compli-
cations may arise from the influence of counter-cation [16] and/or solvent [15], which
have usually been omitted in the discussions for SN2 reactions. It was commonly as-
sumed that the counter-cation is sufficiently far from the nucleophile, so that the counter-
cation/nucleophile may be considered to be a solvent-separated ion-pair. In this regard,
some useful wisdom has been frequently invoked concerning the role of counter-cation and
solvent for SN2 reactions: alkali metal cations are considered to be inefficient as counter-
cation, and protic solvents (water, alcohols) are to be avoided because of the harmful
hydrogen bonding through –OH with the nucleophile. In a series of investigations, how-
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4.0/).
ever, we have demonstrated [17–23] that these well-known concepts are not always true,
showing that using alkali metal salts (such as CsF or KBr) in combination with Lewis base
promoter/solvent (bulky alcohols, oligoethylene glycols, ionic liquids and derivatives
et al.) may lead to excellent SN2 reactions without many side-products (usually with >90%
SN2 yield within several hours).
Molecules 2021, 26, 2947. https://doi.org/10.3390/molecules26102947
https://www.mdpi.com/journal/molecules

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Here, we present the SN2 fluorination promoted by crown ether [23
–
28] using the alkali
metal salt CsF to estimate the efficacy of the promoter and to elucidate the mechanism-. We
employ different types of substrates (1 vs. 2) for comparison. The intramolecular crown ether
1
and the veratrole-Oms substrate are chosen to isolate the effects of substrate structures
on the Gibbs free energy of activation G‡ from other constituents (such as the collision
frequency, orientation of collision, etc.) in the pre-exponential factor in Arrhenius equation
for rate constants. In the SN2 fluorination of crown ether we find that fused reactant 1
proceeds much faster (~99% in 12 h) than that of 2, clearly demonstrating the efficacy of
the intramolecular promoter.
Moreover, we observe that the yield of intramolecular SN2 fluorination of substrate
2
(Veratrole-OMs) almost exactly follows the kinetics of
1 in the presence of 18-crown-
6
3
to near completion in 12 h, indicating that very similar mechanisms are involved
both in intra- and inter-molecular organocatalysis of the crown ether promoter for SN2
fluorination. We examine the mechanisms of fluorination for the reactants to estimate the
role of intramolecular crown ether unit in 1 and the two methoxy groups in 2 for enhancing
the SN2 rates. Organocatalysis of SN2 fluorination of 2 by an independent (intramolecular)
crown ether (18-crown-6), which is a more conventional type of reaction promoted by
crown ether, is also studied. We show that the calculated relative Gibbs free energies of
activation for these reactions are in excellent agreement with the experimentally measured
yields of fluorination. Our calculations also illustrate that the mechanisms of these observed
kinetics are such that the crown ether units act as Lewis base promoters [17–22,29] for SN2
fluorination. Brief discussion is given concerning the role of the metal salt CsF in relation
to whether it reacts as a contact ion pair [30] or not.
2. Materials and Methods
General remarks. Unless otherwise noted, all reagents and solvents were commercially
available. TLC analysis was performed using Merck silica gel 60F254 plates. Visualization
on TLC was monitored by UV light (254 nm). Flash chromatography was performed
with 230–400 mesh silica gel. 1H and 13C NMR spectra were recorded on a 400 MHz
spectrometer (Bruker, Billerica, USA), and chemical shifts were reported in δ units (ppm)
relative to tetramethylsilane. High resolution mass spectra were obtained at the Korea
Basic Science Institute (Daegu, Korea).
Typical Procedure for SN2 Fluorination in Figure 1. CsF (46 mg, 0.3 mmol) was added
to the mixture of substrates 1–3 (0.1 mmol) in CH3CN (1.0 mL). The reaction mixture was
stirred at 80 ◦C. At each time point, 0.1 mL of mixture was sampled. The reaction mixture
was cooled to room temperature and the solvent (CH3CN) was removed under vacuum to
concentrate the product. Ratios of compounds in reaction mixtures were determined using
1H NMR spectroscopy.
4-Fluoropropylbenzo-18-crown 6-ether (1a). According to the typical procedure for
fluorination, 1a (37 mg, 99%) was obtained as a yellow oil after flash column chromatogra-
phy (10% MeOH/MC); 1H NMR (400 MHz, CDCl3)
δ
1.90–2.03 (m, 2H), 2.66 (t, J = 7.7 Hz,
2H), 3.68–3.77 (m, 12H), 3.90–3.93 (m, 4H), 4.12–4.16 (m, 4H), 4.45 (dt, J = 47.3, 6.0 Hz,
2H), 6.70–6.72 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H); 13C NMR(100 MHz, CDCl3)
30.94 (d,
δ
J = 4.8 Hz), 32.27 (d, J = 19.3 Hz), 69.32, 69.49, 69.88, 69.90, 70.90, 70.94, 83.21 (d, J = 164.7 Hz),
114.74, 115.00, 121.22, 134.55, 147.47, 149.15; MS (FAB) 372 (M+), 149 (100); HRMS (FAB)
calculated for C19H29FO6 (M+) 372.1948, found 372.1950.
4-(3-Fluoropropyl)-1,2-dimethoxybenzene (2a). Prepared according to the typical
procedure for fluorination except the use of 18-crown-6 (26 mg, 0.1 mmol), 2a (19 mg, 98%)
was obtained as a colorless oil after flash column chromatography (20% EtOAc/hexane);
1H NMR (400 MHz, CDCl3)
δ
1.92–2.05 (m, 2H), 2.69 (t, J = 7.7 Hz, 2H), 3.85 (s, 3H), 3.87
(s, 3H), 4.47 (dt, J = 47.1, 6.0 Hz, 2H), 6.72–6.74 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H); 13C
NMR(100 MHz, CDCl3)
δ 30.97 (d, J = 4.8 Hz), 32.29 (d, J = 19.3 Hz), 55.88, 55.98, 83.15
(d, J = 163.8 Hz), 111.39, 111.90, 120.37, 133.78, 147.42, 148.98; MS (EI) 198 (M+), 151 (100);
HRMS (EI) calculated for C11H15FO2 (M+) 198.1056, found 198.1057.

Molecules 2021, 26, 2947
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Figure 1. Intra- and inter-molecular 18-crown-6 promoted nucleophilic fluorination in comparison with SN2 fluorination of
the veratrole substrate . (A) Reaction of intramolecular 18-crown-6 integrated mesylate . (B) Reaction of mesylate in
. Quantity of the products was determined using
2
1
2
absence of 18-crown-6. (C) Reaction of mesylate
1H NMR spectroscopy.
2 with in the presence of 3
3. Computational Details
All calculations were carried out by M06-2X [31] density functional theory method
with 6-311G(d,p) [32 33] basis set for C, H, O, S, F atoms and LANL2DZ basis set for
,
Cs atom with their corresponding effective core potential [34] as implemented in G09
software package [35]. The SMD model [36] was used to consider the effects of solvation
by acetonitrile. All frequencies for pre-/post- reaction complexes were confirmed to be
real and one of those for transition state was ascertained to be imaginary. To determine the
unique reaction pathway, the intrinsic reaction coordinate analysis was applied.
4. Results and Discussion
Figure 1 depicts our present scheme designed to verify the effects of crown ethers on
SN2 fluorination. Substrate
1 is a crown ether unit fused with a phenyl ring at which SN2
reaction occurs with the mesylate (-OMs) as the leaving group. We introduce the veratrole

Molecules 2021, 26, 2947
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substrate
2
with -OMs as the leaving group, in which the crown ether moiety is absent, for
comparison. The two methoxy groups in
by the crown ether unit of . First, we carried out intramolecular SN2 fluorination of
promoted by the fused crown ether unit, in comparison with the SN2 fluorination of
Second, we observed the SN2 kinetics for fluorination of in the presence of intermolecular
to compare with intramolecular rate acceleration by
2 are to simulate the promoting effects caused
1
1
2.
2
promotion by a separate crown ether
3
the fused crown ether unit in 1.
The SN2 fluorination yields of 1 and 2 substrates are presented in Figure 1 as functions
of time. We observe several intriguing kinetic features: first, the intramolecular SN2
fluorination was observed to be nearly complete within 12 h, demonstrating the efficacy of
the intramolecular promoter of crown ether, whereas the same reaction of 2 hardly proceeds
(~1% in 24 h). Thus, SN2 fluorination proceeds extremely slowly in the absence of the
promoting effects of the crown ether moiety, indicating that the two methoxy groups in the
veratrole substrate 2 are far less efficient than the crown ether ring for promoting the SN2
fluorination using CsF. These differences in the reactivity of the substrates
1 and 2 are well
accounted for by the Gibbs energies of activation (G‡) for the two cases, as described below.
Second, a more intriguing observation depicted in Figure 1 is that the yield of intermolecular
fluorination of
2 in the presence of the separate promoter 3 (18-crown-6) follows an almost
indistinguishable time evolution of SN2 intramolecular fluorination of 1: Both reactions
arrive at ~80% in 6 h, and at near completion within 12 h. It seems that very similar
mechanisms are involved both in intramolecular 18-crown-6 promoted SN2 fluorination
of
structurally similar pre-reaction complexes and transition states (TSs).
The calculated energetics for SN2 fluorination reactions of and
Figure 2. The Gibbs free energy of activation of SN2 fluorination of and
to be 6.8 and 14.3 kcal/mol, respectively. This clearly accounts for the observed poor yields
of fluorination for relative to that of the intramolecular fluorination of by the much
higher Gibbs free energy of activation of SN2 fluorination of than that of . The TSs in
SN2 fluorination of are depicted in Figure 3 (NMR spectra and Cartesian coordinates of
the pre- and post-reaction complexes and the TSs are given in Supplementary Materials).
In SN2 fluorination of either in close contact
, the nucleophile F− seems to react with
1 and in intermolecular 18-crown-6 promoted fluorination of 2 by 3, probably via the
1
2
are depicted in
2 are calculated
1
2
1
2
1
1
1
1
with (G‡ = 6.85, RCs-F = 3.238 Å, Sub1-I)
, or far away (as compared with RCs-F = 2.836 Å of
CsF in CH3CN) from the counter-cation Cs+ (G‡ = 6.82 kcal/mol, RCs-F = 7.724 Å, Sub1-II)
in the TSs, both of which are predicted to contribute almost equally because of their very
similar Gibbs free energies of activation. For fluorination of the substrates 2, the distance
between Cs+ and F− in the TS is very small (RCs-F = 2.992 Å).
Figure 4 depicts the calculated energetics and structure of the TS for SN2 fluorination
reactions of in the presence of (18-crown-6). It seems that the latter structure formed
between and for intermolecular SN2 fluorination of strongly resembles the TS for
intramolecular SN2 fluorination of shown in Figure 3. From this, the role of 18-crown-6
is clear: the metal salt Cs+F− coordinates to
, just as in SN2 fluorination of , and the O
2
3
2
3
2
1
3
1
atoms in 18-crown-6 are acting as a Lewis base alleviating the Coulombic influence of the
−
counter-cation Cs+ to enhance the nucleophilicity of F , as previously elucidated for other
promoters [17–23] (bulky alcohols, oligoethylene glycols, and ionic liquids).
The calculated Gibbs free energy of activation (6.2 kcal/mol) for fluorination of
the presence of 18-crown-6 shown in Figure 4a is very close to, but slightly lower than
that (6.8 kcal/mol) of in Figure 2. The slightly larger observed yield for fluorination
of presented in Figure 1 may indicate that a small portion of and does not form 1:1
complex. It may also be the results of the fact that the intramolecular case (Figure 2) is more
exothermic than the intermolecular case (Figure 4) (Gibbs free energy of reaction 12.59 vs.
8.38 kcal/mol). It is also noteworthy that in this latter process CsF reacts as a contact ion
pair with RCs-F = 3.072 Å in the TS.
2 in
1
1
2
3
−
−

Molecules 2021, 26, 2947
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Figure 2. Energetics of SN2 fluorination of 1 and 2 using CsF. Gibbs free energy in kcal/mol.
Figure 3. Transition states in SN2 fluorination of 1 and 2 using CsF. Bond lengths in Å.
Figure 4.
(a) Energetics and (b) structure of the transition state for SN2 fluorination of 2 in the presence of 3 (18-crown-6).
Gibbs free energy in kcal/mol, and bond lengths in Å.

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5. Conclusions
In this study, we have demonstrated the excellent efficacy of crown ethers for the
rate enhancement of both intramolecular and intermolecular SN2 fluorination using CsF.
Interestingly, similar mechanisms were shown to work for both processes with comparable
kinetics. The role of the crown ethers as Lewis base promoters interacting with the counter
cation Cs+ to reduce its strong Coulombic influence on the nucleophile F− is in line with
our previous works on the organocatalysis of SN2 reactions. One critical observation
made here is that the crown ethers do not seem to separate counter-cation Cs+ from the
nucleophile in some cases, and that the metal salt CsF may act as an ion pair, in contrast to
the conventional concept of crown ether. This intriguing topic will be discussed in more
detail in our subsequent works.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/
10.3390/molecules26102947/s1. NMR spectra and Cartesian coordinates for all compounds are
available in the Supplementary Materials.
Author Contributions: Conceptualization, S.L. and D.-W.K.; methodology, S.L. and D.-W.K.; soft-
ware, S.L., Y.-H.O.; validation S.L. and D.-W.K.; formal analysis, S.L. and D.-W.K.; investigation,
Y.-H.O., W.Y., C.-H.K., S.-W.J., S.-S.L.; resources, S.L. and D.-W.K.; writing—original draft preparation,
S.L. and D.-W.K.; writing—review and editing, Y.-H.O., W.Y., C.-H.K., S.-S.L.; visualization, Y.-H.O.,
W.Y.; supervision, S.L. and D.-W.K.; project administration, S.L. and D.-W.K.; funding acquisition,
S.L. and D.-W.K.; All authors have read and agreed to the published version of the manuscript.
Funding: This work was financially supported by Korea Research Foundation (NRF-2019R1F1A1057609,
2020R1A2C1009017), the Ministry of Science and ICT (MSIT), the MOTIE (Ministry of Trade, In-dustry
& Energy) and KSRC (Korea Semiconductor Research Consortium) support program (grant code:
10080450), Korea.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: This work was financially supported by Korea Research Foundation (NRF-
2019R1F1A1057609, 2020R1A2C1009017), the Ministry of Science and ICT (MSIT), the MOTIE (Min-
istry of Trade, Industry & Energy) and KSRC (Korea Semiconductor Research Consortium) support
program (grant code: 10080450), Korea.
Conflicts of Interest: The authors declare no conflict of interest.
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