Kinetics of Electrophilic Fluorinations of Enamines and Carbanions: Comparison of the Fluorinating Power of N-F Reagents

Article abstract of DOI:10.1021/jacs.8b07147

Kinetics of the reactions of enamines and carbanions with commonly used fluorinating reagents, N-fluorobenzenesulfonimide (NFSI), N-fluoropyridinium salts, Selectfluor, and an N-fluorinated cinchona alkaloid, have been investigated in acetonitrile. The reactions follow second-order kinetics, and from the measured rate constants one can derive that the fluorinations proceed via direct attack of the nucleophiles at fluorine, not by SET processes. Correlations of the fluorination rates with the pK_aH values of the nucleofugal leaving groups and the calculated fluorine plus detachment energies are discussed. The rate constants for the reactions with deoxybenzoin-derived enamines follow the linear free energy relationship log k₂(20 °C) = s_N(N + E) which allows the empirical electrophilicity parameters E for these fluorinating agents to be derived from the measured rate constants and the tabulated N and s_N parameters for the nucleophiles. Though the deviations of the measured rate constants from those calculated by this relationship are larger than for reactions of C_sp2-centered electrophiles with nucleophiles, it is shown that the electrophilicity parameters E reported in this work are able to rationalize known fluorination reactions and are, therefore, recommended as guide for designing new electrophilic fluorinations.

Full text of DOI:10.1021/jacs.8b07147

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Kinetics of Electrophilic Fluorinations of Enamines and Carbanions:
Comparison of the Fluorinating Power of N−F Reagents
Daria S. Timofeeva, Armin R. Ofial, and Herbert Mayr*
̈
̈
̈
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13, 81377 Munchen, Germany
S
* Supporting Information
ABSTRACT: Kinetics of the reactions of enamines and carbanions
with commonly used fluorinating reagents, N-fluorobenzenesulfon-
imide (NFSI), N-fluoropyridinium salts, Selectfluor, and an N-
fluorinated cinchona alkaloid, have been investigated in acetonitrile.
The reactions follow second-order kinetics, and from the measured
rate constants one can derive that the fluorinations proceed via direct
attack of the nucleophiles at fluorine, not by SET processes.
Correlations of the fluorination rates with the pKaH values of the
nucleofugal leaving groups and the calculated fluorine plus detach-
ment energies are discussed. The rate constants for the reactions with
deoxybenzoin-derived enamines follow the linear free energy
relationship log k2(20 °C) = sN(N + E) which allows the empirical
electrophilicity parameters E for these fluorinating agents to be derived from the measured rate constants and the tabulated N
and sN parameters for the nucleophiles. Though the deviations of the measured rate constants from those calculated by this
relationship are larger than for reactions of Csp2-centered electrophiles with nucleophiles, it is shown that the electrophilicity
parameters E reported in this work are able to rationalize known fluorination reactions and are, therefore, recommended as
guide for designing new electrophilic fluorinations.
generally more stable, safer, and more easily to handle, and
they are able to oxidize and fluorinate many substrates under
mild conditions.
INTRODUCTION
■
Since fluorine significantly affects the physical, chemical, and
biological properties of organic molecules, fluorinated
compounds have been gaining increasing importance in
many fields such as agrochemistry,1 medicinal chemistry,2
and materials science.3 For that reason, a wide variety of
methods to synthesize organofluorine compounds have been
developed during the past decades.4 Initially, molecular
fluorine (F2),5 perchloryl fluoride (FClO3),6 xenon difluoride
(XeF2),7 trifluoromethyl hypofluorite (CF3OF),8 and various
acyl9 and perfluoroacyl hypofluorites10 (CH3COOF and
CF3COOF) were the most common reagents available for
electrophilic fluorination. Handling these reagents requires
special techniques, as they are highly toxic and very reactive,
which also hampers their use for asymmetric synthesis.
In order to overcome these disadvantages, new electrophilic
fluorination reagents containing N−F bonds were developed.11
Two types of N−F reagents can be differentiated: neutral
(R2NF) compounds on one side and quaternary ammonium
(R3N+F A−) and pyridinium salts with weakly basic counter-
ions on the other. The discovery of N−F reagents, such as N-
fluorobenzenesulfonimide (NFSI, 1),12 and analogues,13 N-
fluoropyridinium salts (2),14 N-fluoroquinuclidinium salts,15
and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (3, well-known as Selectfluor or F-
TEDA-BF4),16 resulted in the rapid progress of electrophilic
fluorinations. Compared to O−F and other types of previously
used electrophilic fluorinating reagents, N−F reagents are
A significant step in the development of asymmetric
fluorinations17 was the introduction of the N-fluoroammonium
salts of cinchona alkaloids, which can either be isolated as
stable salts or generated in situ from the corresponding
cinchona alkaloids and various commercially available
fluorinating reagents.18 Thus, the chiral cinchona-derived
reagents serve as cheap sources of chirality, which are easier
to synthesize than N-fluorocamphorsultam and related
structures.19 While preparation of the latter requires several
steps and the use of elemental F2, the cinchona alkaloid derived
N-fluoroammonium salt 4 can be obtained by transfer
fluorination of quinine by N-fluorobenzenesulfonimide follow-
ing the procedure by Cahard.18c Gouverneur and co-workers20
have recently developed new classes of chiral N−F reagents
with the dicationic DABCO core and derivatives of ethano
̈
bridged Troger’s bases.
Several attempts to rank electrophilic fluorination agents
with respect to relative reactivities have been reported.
Gilicinski et al.21 found a correlation between the peak
potentials of the first one-electron reduction (Erped) of the N−F
reagents and their reactivities in synthetic fluorinations (Figure
1).
Received: July 6, 2018
© XXXX American Chemical Society
A
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Chart 1. Electrophilic Fluorinating N−F Reagents Studied
in This Work
Figure 1. Peak reduction potentials Erped (in MeCN) of electrophilic
fluorinating N−F reagents.
Sudlow and Woolf22 criticized this work due to uncertainties
in the measurements and interpretation of the electrochemical
data and suggested a thermodynamic ordering based on the
calculated F+ detachment enthalpies, which correlated with
LUMO energies of the N-fluoropyridinium ions. Related
electrochemical studies for six recently used fluorinating
reagents with the tetrafluoroborate counterion have been
reported by Evans et al.23 Umemoto and co-workers discussed
the relationship between the variable fluorinating power of N-
fluoropyridinium salts and their 19F NMR chemical shifts.24
Togni et al. determined the relative fluorinating activity of
various fluorinating N−F reagents in Ti(TADDOLato)-
catalyzed fluorinations of β-keto esters by competitive
halogenations (Figure 2).25
Chart 2. Reference Nucleophiles Used in This Work and
Their Nucleophilicity Parameters N and sN in Acetonitrile
and DMSO27
Figure 2. Relative fluorination rates derived from competition
experiments (krel from ref 25).
Assuming that the fluorinating power of Y−F reagents is
related to the F+ detachment energy (FPD) defined by eq 1,
Xue, Cheng, and co-workers calculated ΔH° (eq 1) for 130
N−F reagents at the (SMD)M06-2X/6-311++G(2d,p)//M05-
2X/6-31+G(d) level of theory in MeCN and CH2Cl2
solution.26
FPD
Y − F ⎯⎯⎯→ Y− + F+
(1)
ΔH°
In this article we report on the first kinetic investigations of
the reactions of the most common commercially available
fluorinating reagents 1−4 (Chart 1) with carbon nucleophiles
and show how the rate constants for the reactions with the
enamines 5 and carbanions 6 (Chart 2) can be combined with
the nucleophilicity parameters N (sN)27 to define the synthetic
potential of these fluorinating agents.
RESULTS AND DISCUSSION
■
Product Analysis. To establish the course of the reactions,
which were investigated kinetically, we have studied the
products of some representative fluorination reactions. As
B
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shown in Table 1, treatment of the deoxybenzoin-derived
enamines 5a and 5f with 1.05 equiv of the fluorinating agents
1−3 in acetonitrile at room temperature and subsequent
hydrolysis gave mixtures of the mono- and difluorinated
deoxybenzoins 7 and 8, the ratio of which was determined by
integration of the 19F NMR spectra of the crude reaction
mixtures. Due to the formation of the difluorinated
deoxybenzoin 8 and other side products, 1.05 equiv of the
fluorinating agents were not sufficient for full conversion of the
enamines.
Reactions of enamines with electrophilic fluorinating
reagents have previously been reported to give mono- and
difluorinated ketones after hydrolysis,28 and the reactions of
enamines with two equivalents of Selectfluor (3) in the
presence of Et3N have been described as a synthetic method
for the formation of difluorinated carbonyl compounds.28a
Dilman et al. reported the fluorocyanation of enamines
involving the electrophilic fluorination of the CC bonds
with N−F reagents to form fluoroiminium ions, which were
trapped by cyanide ions.29
In the reaction of the enamine 5a with 2b (Table 1, entry 3),
the fluorinated ketones 7 and 8 were accompanied by the 2-
substituted pyridine 9. Formation of 9 can be explained by the
mechanism shown in Scheme 2. The unsubstituted N-
fluoropyridinium ion 2b is an ambident electrophile, which is
not only attacked at the fluorine atom but also at the 2-position
of the pyridinium ring. HF-elimination from the intermediate
dihydropyridine and hydrolysis yields ketone 9. The
observation that nucleophilic attack at the chlorinated 2-
positions of 2c does not occur is in line with the observation
that C−H positions are more reactive than C−Cl positions in
nucleophilic aromatic and vinylic substitutions.30
Table 1. Reactions of the Enamines 5a and 5f with N−F
Reagents in Acetonitrile at 20 °C
fluorination products
a
b
c
c
entry enamine
N−F reagent
crude (7/8)
7 (%)
8 (%)
1
2
3
4
5
5a
5a
5a
5f
NFSI (1)
2a-BF4
2b-BF4
2c-BF4
77/23
77/23
74/26
91/9
95/5
55
43
28
78
80
d
8
Scheme 2. Mechanism of the Reaction of the Pyridinium
Salt 2b-BF4 with Enamine 5a
5f
Selectfluor (3)
a
b
A slight excess of the N−F reagent (1.05 equiv) was used. Product
ratio as determined from the 19F NMR spectrum of the crude
c
d
product. Yields refer to the isolated products. In addition, 9 was
isolated (11% yield).
As shown in Scheme 1, electrophilic fluorination of the
enamines first gives monofluorinated iminium ions, which may
be deprotonated by the amine, amide, or pyridine released
from the N−F reagents 1−3 during F+ transfer. The resulting
monofluorinated enamines can be fluorinated by another
molecule of fluorinating agent to give the difluorinated
iminium salts, and hydrolysis yields a mixture of the ketones
7 and 8.
Treatment of the deep-pink solution of the potassium salt of
the diethyl malonate 6b-H with 1 (NFSI, 1.1 equiv) or N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (2a-BF4, 1.1
equiv) at 20 °C led to complete fading of the color within a
few minutes. After workup of the reaction mixture with 2 M aq
HCl, the crude 2-fluorinated diethyl malonate 10 was
obtained, purified by column chromatography, and charac-
terized by NMR spectroscopy and mass spectrometry (Scheme
3).
Scheme 1. Mechanism of the Fluorination of the Enamines
Since reactions of the fluorinating reagents 2b, 2c, and 3
with carbanions 6a−f were too fast for kinetic measurements,
we have not studied the products of these reactions. Reactions
of various C-nucleophiles with N-fluoropyridinium tetrafluoro-
borate 2b-BF4 have previously been reported to give products
Table 1 shows that the reactions of the enamine 5a with the
less reactive fluorinating reagents 1, 2a, and 2b yielded mono-
and difluoro-substituted products in a ratio of 3/1 (entries 1−3
in Table 1), while the reactions of the enamine 5f with the
more reactive fluorinating reagents 2c and 3 gave the
monofluorinated ketone 7 predominantly, accompanied by
only a small amount of the difluorinated ketone 8. This
difference may be explained by the fact that 2,6-dichloro-
pyridine (from 2c) and DABCO-derived ammonium ions
(from 3) are weak bases, which do not efficiently convert the
monofluorinated iminium ions into the fluorinated enamines.
Therefore, in entries 4 and 5 of Table 1 the second fluorination
plays a minor role.
Scheme 3. Reactions of the N−F Reagents 1 and 2a-BF4
with Nucleophile 6b-K
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arising from pyridylation, rather than the fluorinated
products.31 Attack at the 2-position of the N-fluoropyridinium
ion 2b is also preferred by sulfur-, oxygen-, and nitrogen-
centered nucleophiles; reactions with N-fluoropyridinium salts
were, therefore, recommended as routes to 2-substituted
pyridines.32 Umemoto and co-workers showed that 2,4,6-
trimethyl-substituted N-fluoropyridinium triflate (2a-OTf)
afforded only the fluorinated product in the reaction with
diethyl phenylmalonate. In contrast, 2- and/or 4-unsubstituted
N-fluoropyridinium salts reacted with the formation of pyridyl
derivatives as byproducts.14e
Table 2. Second-Order Rate Constants k2 for the Reactions
of Fluorinating N−F Reagents 1−4 with Enamines 5a−h
and Carbanions 6a−f in MeCN at 20 °C
Kinetic Investigations. The kinetics of the reactions of
the reference nucleophiles (Chart 2) with the fluorinating
reagents 1−4 were studied at 20 °C in acetonitrile solution. All
reactions were monitored photometrically by following the
disappearance of the enamines 5 or the carbanions 6 at or close
to their absorption maxima (see the Supporting Information).
Due to the low stability and poor solubility of the isolated
carbanion salts (6a−f)-K in acetonitrile, these carbanions were
generated in acetonitrile solution prior to each kinetic
measurement by treatment of the conjugate CH acids 6-H
with potassium tert-butoxide (1.05 equiv). To simplify the
kinetics, the fluorinating agents were used in sufficient excess
(≥10 equiv) to achieve pseudo-first-order conditions (eq 2).
−d[Nu]/dt = kobs[Nu], kobs = k2[E]0
(2)
An example for the resulting monoexponential decays of the
UV−vis absorbances of the minor components 5 or 6 is shown
in Figure 3 for the reaction of 5a with 1 (NFSI). The first-
Figure 3. Exponential decay of the absorbance of enamine 5a (c0 =
1.06 × 10−4 M) at 315 nm during its reaction with the N−F reagent 1
(NFSI, c0 = 2.21 × 10−3 M). Inset: Correlation of the rate constants
kobs with [1] in MeCN at 20 °C. The tagged data point refers to the
depicted absorption-time trace.
order rate constants kobs (s−1) were derived by least-squares
fitting of the exponential function At = A0 exp(−kobst) + C to
the time-dependent absorbances of the reference nucleophiles.
The correlations of kobs with the concentrations of the
electrophiles were linear for all reactant combinations, as
illustrated by the inset of Figure 3. The slopes of such
correlations were used to derive the second-order rate
constants k2 for the reactions of electrophilic fluorinating
reagents 1−4 with the reference nucleophiles 5 and 6 in
acetonitrile (see the Supporting Information for the individual
correlations of all investigated reactions). Table 2 summarizes
the obtained second-order rate constants for electrophilic
fluorinations.
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As shown in Table 2, the rate constants of the reactions of
N-fluoropyridinium salt 2a with carbanions 6b,c increased by a
factor of 2.3 when tetrafluoroborate ions were replaced by
triflate counterions. In contrast, enamine 5a reacts even 1.3
times faster with 2a-BF4 than with 2a-OTf. Since the influence
of the counterions on the rates of the fluorinations is small
compared to the substituent effects in the pyridinium ions we
will neglect them in the following discussion.
Table 3 compares the influence of 18-crown-6 ether on the
second-order rate constants of the reactions of N−F
Table 3. Second-Order Rate Constants for the Reactions of
Fluorinating N−F Reagents 1 and 2a with 6b-K (20 °C,
MeCN) with or without Added 18-Crown-6 Ether
k2 (M−1 s−1
)
a
b
N−F reagent
6b-K
6b-K + 18-c-6
krel
1
7.71 × 102
1.34 × 103
2.92 × 103
8.35 × 102
1.66 × 103
3.04 × 103
1.1
1.2
1.0
2a-BF4
2a-OTf
a
In the presence of 18-crown-6 ether (1.05 equiv with respect to 6b-
b
K). krel = k2(K+/18-c-6)/k2(K+).
fluorinating reagents with 6b-K. The rate constants of the
reactions with 1 (NFSI) and N-fluorocollidinium triflate (2a-
OTf) with and without added crown ether agree within
experimental error, while the fluorination with the tetrafluor-
oborate salt of 2a is accelerated by a factor of 1.2 by the 18-
crown-6 ether.
Correlation Analysis. During the last decades, we have
shown that a large variety of reactions of π-electrophiles with
n-, π-, and σ-nucleophiles can be described by eq 3
Figure 4. Correlations of (log k2)/sN for the reactions of fluorinating
N−F reagents 1−3 with the enamines 5 against the nucleophilicity
parameters N of 5 (MeCN, 20 °C). For all correlations, a slope of 1.0
was enforced, as required by eq 3 (individual correlations for all
electrophiles investigated in this work are shown in the Supporting
Information).
log k2(20°C) = sN(N + E)
(3)
where k2 is the second-order rate constant, sN and N are
solvent-dependent nucleophile-specific parameters, and E is an
electrophile-specific parameter.33 On the basis of this linear
free-energy relationship, we have created a comprehensive
nucleophilicity scale covering more than 30 orders of
magnitude.27g
To examine the applicability of eq 3 for the fluorination
reactions studied in this work, (log k2)/sN for the reactions of
1−3 with the deoxybenzoin-derived enamines 5a−f was
plotted against the nucleophilicity parameters N listed in
Chart 2. Since the slopes of these correlations deviated only
marginally from 1.0, we abstained from adding an extra
electrophile-specific susceptibility parameter sE, as suggested
for SN2 reactions,34 and enforced a slope of 1 for the
correlations shown in Figure 4. The fact that the individual
data points are close to the corresponding correlation lines
shows that these reactions follow eq 3, and the intercepts (at N
= 0) correspond to the electrophilicity parameters E for the
fluorinating N−F reagents 1−3. The E values given in Figure 4
show that Selectfluor (3) and 1-fluoro-2,6-dichloropyridinium
ions 2c are of similar electrophilicity, three powers of ten more
reactive than NFSI (1), which is followed by the unsubstituted
N-fluoropyridinium ion 2b and the least reactive collidine-
derived fluorinating reagent 2a, which is 2 orders of magnitude
less reactive than 1.
Figure 5. Correlations of the second-order rate constants (log k2) for
the reactions of enamines 5a−d with the 4,4′-(dimethylamino)-
substituted benzhydrylium ion (from ref 27a) and the fluorinating
reagents 1 and 3 (MeCN, 20 °C) with the Hammett substituent
constants σp (from ref 35).
reaction constants of ρ = 0.63 and 0.80 reach only about
half the amount of the corresponding ρ for the reactions with
the 4,4′-(dimethylamino)-substituted benzhydrylium ion,27a
indicating that the rates of the electrophilic fluorinations are
less sensitive to variation of the nucleophile than the rates of
the reactions with carbenium ions.
Figure 5 illustrates that the rate constants of the electrophilic
fluorinations of the X-substituted deoxybenzoin-derived
enamines with NFSI (1) and Selectfluor (3) correlate linearly
with Hammett substituent constants σp.35 The resulting
E
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When the electrophilicity parameters E of the fluorinating
agents 1−3, originating from the rate constants of their
reactions with the deoxybenzoin-derived enamines 5a−f
(Figure 4), are employed to calculate the second-order rate
constants for the fluorinations of the β-aminostyrenes 5g,h,
one obtains values which are 14−55 fold higher than measured
(Table 4). Though these deviations are within the tolerance
Table 4. Experimental and Calculated Second-Order Rate
Constants for the Reactions of Fluorinating N−F Reagents
1−3 with β-Aminostyrenes 5g,h at 20 °C in MeCN
a
N−F reagent nucleophile ke2xp (M−1 s−1
)
kc2alcd (M−1 s−1
)
kc2alcd/ke2xp
1
5g
5g
5g
5g
5g
5h
5h
5h
2.42 × 102
9.99
1.34 × 104
3.90 × 102
1.06 × 103
3.32 × 106
3.88 × 106
4.71 × 102
1.94 × 105
2.30 × 105
55
39
23
14
48
20
19
30
2a-BF4
2b-BF4
2c-BF4
3
4.53 × 101
2.40 × 105
8.14 × 104
2.38 × 101
9.97 × 103
7.75 × 103
1
2c-BF4
3
a
Calculated by using eq 3, N and sN from Chart 2, and E from Figure
Figure 6. Correlations of (log k2)/sN versus the nucleophilicity of the
enamines 5 (determined in MeCN) and carbanions 6 (determined in
DMSO) for their reactions with NFSI (1) in MeCN at 20 °C. Both
correlation lines are fixed to a slope of 1.0, as required by eq 3.
4.
limit of eq 3, the constantly higher calculated rate constants
indicate a common origin: The calibration of the nucleophi-
licities of the enamines 5a−h was based on reactions with
benzhydrylium ions, which are electrophiles of intermediate
steric demand. Since the fluorinating agents are sterically less
demanding than benzhydrylium ions, the relative reactivities of
the highly substituted enamines 5a−f and the less substituted
enamines 5g,h will be less affected by steric effects in reactions
with the fluorinating agents than in reactions with benzhy-
drylium ions. As the electrophilicities E of the fluorinating
agents were derived from their reactions with the enamines
5a−f, one can explain why the rate constants with the sterically
less demanding β-aminostyrenes 5g,h are calculated too high.
Limitations of eq 3 are illustrated in Figure 6, which depicts
that the reactions of 1 with the deoxybenzoin-derived
enamines 5a−f and the carbanions 6a−e follow separate
correlations. Application of E(1), derived from reactions of 1
with enamines 5a−f, for calculating the rate constants of
reactions of 1 with carbanions 6a−e yields second-order rate
constants k2, which are 2.5−4 orders of magnitude larger than
measured. Is this discrepancy due to the fact that the rate
constants for the reactions of 1 with 6a−e in acetonitrile were
used in a correlation along with the N parameters of 6a−e,
which had been derived from the kinetics of reactions in
DMSO?
Information) is so close to that in DMSO (N = 20.00, sN =
0.71, Chart 2) that this agreement of the carbanion reactivities
in acetonitrile and DMSO justifies to generally use the N and
sN parameters for carbanions in DMSO when correlating rate
constants measured in acetonitrile.
For answering this question, we have investigated the
kinetics of the reactions of the carbanions 6a and 6f with the
reference electrophiles 11 (benzhydrylium ions and quinone
methides) in acetonitrile solution and compared the resulting
second-order rate constants with those previously reported in
DMSO. Table 5 shows that the reactions of 6a with the
benzhydrylium ions 11a and 11b are 18- and 12-fold faster in
acetonitrile than in DMSO solution. Moreover, the reactions of
carbanion 6f with the quinone methides 11c−g are only 1.7 to
4 times faster in acetonitrile than in DMSO. These differences
are too small to assign the observation of separate correlation
lines in Figure 6 to a solvent effect. The nucleophilicity
parameter of carbanion 6f in acetonitrile derived from the rate
constants in Table 5 (N = 20.43, sN = 0.73, Supporting
Figure 7. Correlations of (log k2)/sN versus the nucleophilicity of the
enamines 5 (determined in MeCN) and carbanions 6 (determined in
DMSO) for their reactions with 2a (MeCN, 20 °C). Both correlation
lines are fixed to a slope of 1.0, as required by eq 3.
Figure 7 shows that the correlation lines for the reactions of
the N-fluorocollidinium ion 2a with enamines and carbanions
are only slightly separated that one might even consider to
construct a single correlation line, that is, derive E(2a) from all
available rate constants (reactions with enamines and
carbanions). However, the usage of different sets of reference
nucleophiles for the characterization of the different fluorinat-
F
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Table 5. Comparison of the Second-Order Rate Constants for the Reactions of Carbanions 6a,f with Benzhydrylium Ions and
Quinone Methides in Acetonitrile (kA2N) and DMSO (k2DMSO) at 20 °C
a
b
c
entry
carbanion
electrophile
E
kA2N (M−1 s−1
)
kD2 MSO (M−1 s−1
)
kA2N/kD2 MSO
1
2
3
4
5
6
7
6a
6a
6f
6f
6f
6f
6f
11a
11b
11c
11d
11e
11f
−9.45
3.44 × 105
8.24 × 104
9.10 × 105
5.37 × 104
6.31 × 103
1.99 × 103
1.51 × 103
1.89 × 104
6.73 × 103
2.63 × 105
1.35 × 104
3.68 × 103
8.80 × 102
4.90 × 102
18
12
−10.04
−12.18
−14.36
−15.03
−15.83
3.5
4.0
1.7
2.3
3.1
11g
−16.11
a
b
c
From ref 33b,c,g. For details see the Supporting Information. Rate constants were taken from ref 27b (for 6a) and ref 27f (for 6f).
ing agents would reduce the comparability of the correspond-
ing electrophilicity parameters. We decided, therefore, to stay
consistently with the enamine-derived electrophilicity param-
eters E (as shown in Figure 4) and emphasize that deviations
up to 4 orders of magnitude have to be tolerated when the E
parameters for 1−4 are used to calculate rate constants for the
fluorination of carbanions.
Which Factors Control the Fluorinating Power of the
Reagents 1−4? The question whether electrophilic fluorina-
tions with N−F reagents proceed via SN2 type mechanisms or
via single electron transfer (SET) has previously been
discussed (Scheme 4).21,36 Radical clock experiments36a and
Scheme 4. Possible Mechanistic Pathways of Electrophilic
Fluorinations
Figure 8. Plot of measured rate constants log k2 for the reactions of
N−F fluorinating reagents 1−3 with the enamine 5d against the
corresponding cathodic peak potentials Erped (taken from ref 23).
b
aNFSI (1) not included in the correlation. Rate constant (log k2)
calculated by applying N and sN (from Chart 2) and E (from Figure
4) in eq 3.
potentials of 1−321 (see Figure 1) were used to calculate the
Gibbs energy for electron transfer ΔG°ET by eq 4.
ΔGET = F(Eox − Ered
)
°
(4)
comparison of observed rate constants with those expected for
SET processes36b led Differding and Wehrli to the conclusion
that electrophilic fluorinations of typical silyl enol ethers,
malonate, and enolate ions with an N-fluorosultam generally
proceed by direct nucleophilic attack at fluorine, while electron
transfer occurs only in rare cases. By using a cyclopropyl
radical probe, Wong and co-workers excluded an SET
mechanism for the reactions of vinyl ethers with Selectfluor
(3) because products of cyclopropane ring-opening were not
observed.36e
Our kinetic data confirm these conclusions. Figure 8 shows
that the rate constants for the reactions of the enamine 5d with
the cationic reagents 2−3 (Table 1) correlate linearly with the
corresponding reduction potentials,23 while NFSI (1) reacts
much faster than expected from the depicted correlation for
the other fluorinating agents.
Equation 3 was then applied to calculate the second-order
rate constants at 20 °C for the polar reactions of the
fluorinating agents 1−3 with the enamines 12a−f from the E
values in Figure 4 and the corresponding N and sN
parameters38a given in Table 6. Conversion of the second-
order rate constants for the polar fluorination reactions into
the Gibbs energies of activation ΔG‡P was performed with the
Eyring equation.39a
Table 6 shows and Figure 9 illustrates that the fluorinations
of the enamines 12a−f with all fluorinating agents proceed
with activation energies ΔGP‡, which are smaller than the Gibbs
energies of electron transfer ΔG°ET. If one considers that the
energy of activation for electron transfer ΔG‡ET must be greater
than ΔGE°T (Figure 10) we can conclude that none of the
reactions considered proceeds via SET.39b,c
In line with previous analyses36b we thus conclude that the
electrophilic fluorinations with 1−4 proceed in an SN2 type
mechanism in which the rate-determining step includes
cleavage of the N−F bond. Since nucleofugality is often
correlated with the basicity of the leaving group, we have also
examined the relationships between the fluorinating activities
Since oxidation potentials for the nucleophiles in Chart 2,
which we investigated in this work, are not available, we
examined the mechanistic alternatives for the fluorinations of
the enamines 12a−f (Table 6). The reported anodic peak
potentials of the enamines 12a−f37 and peak reduction
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Table 6. Calculated Gibbs Energies for Electron Transfer from the Enamines 12a−f to the N−F Reagents 1−3, ΔG°ET (from eq
4), Compared with Gibbs Energies of Activation for the Polar Fluorine Transfer from the N−F Reagents 1−3 to the Enamines
a
12, ΔG‡P (from eq 3)
1
2a
2b
3
b
c
enamine
N/sN
Eopx,
ΔGE°T
ΔG‡P
ΔGE°T
ΔG‡P
ΔGE°T
ΔG‡P
ΔGE°T
ΔG‡P
12a
12b
12c
12d
12e
12f
15.91/0.86
15.06/0.82
13.41/0.82
14.91/0.86
13.36/0.81
11.40/0.83
0.37
0.44
0.56
0.36
0.47
0.57
111
118
129
110
121
130
36
41
49
41
49
58
106
113
125
105
116
125
45
51
58
50
59
67
81
88
99
80
91
100
43
48
56
48
56
65
40
46
58
39
49
59
20
26
34
25
35
43
a
b
Gibbs energies are in kJ mol−1. In CH2Cl2, taken from ref 38a; N and sN for neutral π-systems are almost identical in dichloromethane and
c
acetonitrile (as shown in ref 38b). Anodic peak potential Eopx (in V vs SCE) in MeCN at 25 °C, taken from ref 37.
Figure 10. Gibbs energy profile for the polar and electron-transfer
mechanism of the reaction of the cyclic enamine 12a with NFSI (1).
Figure 9. Comparison of the calculated Gibbs energies of electron
transfer (ΔGE°T) and the Gibbs energies of activation for the polar
mechanism (ΔG‡P) of the reactions of cyclic enamines 12a−f with (a)
NFSI (1), (b) the N-fluorocollidinium ion (2a), (c) the N-
fluoropyridinium ion (2b), and (d) Selectfluor (3) (data from
Table 6).
Figure 11. Correlation between the rate constants (log k2) for the
reactions of fluorinating N−F reagents 1−4 with the enamine 5d in
MeCN against the acidities of the corresponding N−H compounds in
water (taken from ref 41). aNot used for the correlation. bRate
constant (log k2) calculated by applying N and sN (from Chart 2) and
E (from Figure 4) in eq 3.
of 1−4 with the pKa values of the conjugate acids of the
nucleofuges.
Figure 11 shows a fair correlation between the electrophilic
reactivities of 1 and 2 with the basicities of the nucleofuges
(leaving groups). The positive deviation of 4 from this
correlation line reflects the lower intrinsic barrier in reactions
of tertiary amines (Nsp3) compared to pyridines (Nsp2), which
has previously been observed for reactions of electrophiles with
amines and pyridines of equal basicity40 as well as for the
corresponding reverse reactions.40b
Enthalpies for the heterolytic cleavage of N−F reagents, so-
called fluorine plus detachment (FPD) energies (eq 1), were
used by Christe and Dixon in 1992 as a quantitative measure
for the oxidizing strengths of “oxidative fluorinators”.42 As
mentioned in the introduction, Xue and co-workers have
recently calculated FPDs for 130 fluorinating agents, including
H
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those for compounds 1−4. Figure 12 shows that the
electrophilic reactivities of the N-fluorinated pyridinium ions
Figure 12. Correlation between the rate constants (log k2) for the
reactions of fluorinating N−F reagents 1−4 with the enamine 5d
against the corresponding FPD values (eq 1) calculated in MeCN
(taken from ref 26). Only the data for 2a−c were used to calculate the
correlation line. aRate constant (log k2) calculated by applying N and
sN (from Chart 2) and E (from Figure 4) in eq 3.
2a−c correlate linearly with their FPD values. In analogy to the
correlation depicted in Figure 11, also Figure 12 indicates that
the F−Nsp3 reagents 3 and 4 react significantly faster than Nsp2
reagents of equal FPDs.
Figure 13. Comparison of the rate constants (log k2) for the reactions
of the fluorinating N−F reagents 1−4 with the deoxybenzoin-derived
a
enamine 5d (MeCN, 20 °C). Rate constant (log k2) calculated by
applying N and sN (from Chart 2) and E (from Figure 4) in eq 3.
The role of intrinsic barriers (proportional to reorganization
energies)43 is best illustrated by the fact that compounds 2b, 1,
and 3, all of which have the same FPD value, differ by 4 orders
of magnitude in electrophilicity (Figure 12). Whereas the
thermodynamic FPD values thus cannot directly be correlated
with rate constants, they can be used for predicting equilibrium
constants: Though 4 is a stronger electrophile than 1, 4 has
been synthesized by the reaction of quinine with 1, in line with
the higher F+ affinity of quinine shown in Figure 12.
corresponding thermodynamic quantities due to the lower
intrinsic barriers of their reactions. Lower intrinsic barriers for
the reactions of F−N(sp3) reagents also explain why 4 is a
faster fluorinating agent than 1, though 4 can be synthesized by
the reaction of quinine with 1 in acetonitrile.
The rate constants of the reactions of 1−4 with the
enamines 5a−f follow the linear free energy relationship (eq 3)
and were used to derive the electrophilicity parameters E for
these fluorinating agents. The previously known qualitative
ranking of the strengths of the fluorinating agents 1−4 has thus
been quantified. In addition, the E values of 1−4 can now be
combined with the tabulated reactivity parameters N and sN of
C-nucleophiles27g to derive absolute rate constants for
electrophilic fluorinations by eq 3. In this way the electro-
philicity parameters E provide a quantitative basis for selecting
suitable fluorinating agents and conditions for desired synthetic
transformations, which will be illustrated by the following
examples.
On the right of Figure 14, the electrophilic reactivities of 1−
3 are compared with those of C-centered electrophiles. The
left column of Figure 14 orders C-nucleophiles with increasing
strengths from top to bottom and arranges them in a way that
(E + N) = −3 for electrophiles and nucleophiles that are
located at the same horizontal level. Since the nucleophile-
specific susceptibilities sN are typically in the range of 0.7 < sN
< 1.0, eq 3 predicts second-order rate constants from 10−3 to
10−2 M−1 s−1 at 20 °C for such electrophile-nucleophile
combinations, which corresponds to half-reaction times of
approximately 1 h for 0.1 M solutions of the reactants.
Accordingly, fluorinating reagents can be expected to undergo
noncatalyzed reactions at room temperature with those
nucleophiles located below them, while reactions with
nucleophiles positioned higher in Figure 14 do not occur or
require harsher conditions.
CONCLUSIONS
■
The deoxybenzoin-derived enamines 5a−f have suitable
nucleophilicities for determining the electrophilic reactivities
of the fluorinating reagents 1−4 by direct rate measurements.
As shown in Figure 13, Selectfluor (3) and the 2,6-dichloro-1-
fluoro-pyridinium ion (2c) are by far the most reactive N−F
reagents of this series, followed by the N-fluorinated quinine 4
and NFSI (1). The pyridinium ions 2a and 2b are at the lower
end of the scale, 5 orders of magnitude less reactive than
Selectfluor (3). Since the parent N-fluoropyridinium ion 2b
may also be attacked at C-2 of the pyridinium ion, the N-
fluoro-substituted collidinium ion 2a can be considered as the
reagent of choice, when a mild fluorinating reagent is needed.
In agreement with Togni’s competition experiments,25 our
direct rate measurements also showed Selectfluor (3) to be the
most reactive fluorination reagent, but in contrast to Togni’s
ranking, which indicated that 3 reacts 18 times faster with
carbanions than 2c, our direct rate measurements reveal
comparable fluorinating activities of 2c and 3.
Though the nature of the counterions of the cationic
fluorinating agents sometimes affects the isolable yields of the
fluorinations, counterions have only a small effect on the rates
of the fluorine transfer. Whereas the electrophilic reactivities of
the N-fluoropyridines 2a−c correlate with the corresponding
pKa values and FPD energies, reagents 3 and 4 with F−N(sp3)
functionalities react much faster than expected from the
I
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Figure 14. Ranking of the electrophilic fluorinating reagents 1−3 in the electrophilicity scale and scope of their reactions with nucleophiles
(nucleophilicity parameters N in CH2Cl2 if not mentioned otherwise, N and E were taken from ref 27g).
According to their electrophilicity parameters none of the
N−F reagents in Figure 14 should be able to attack anisole,
styrene, or phenylacetylene at ambient temperature. In line
with this prediction heating to 70 °C for 3 h was needed to
fluorinate anisole with Selectfluor (3) or N-fluoropyridinium
salt 2c with 47% and 56% yield, respectively.44 The
fluorination of benzene, anisole, and other arenes with 3 was
achieved at 0−40 °C in dichloromethane in the presence of
trifluoromethanesulfonic acid. Protonated trifluoromethanesul-
fonyl hypofluorite was suggested to be the actual fluorinating
reagent in these reactions.45 The noncatalyzed fluorination of
anisole with NFSI (1) required harsh conditions (100%
conversion after 5h at 150 °C with 22 equiv of anisole).12
Reactions of 1,3-dimethoxybenzene (N = 2.48) with
Selectfluor (3) and NSFI (1) were accomplished by heating
to 85−90 °C for 1−8 h under solvent-free conditions to yield
1-fluoro-2,4-dimethoxybenzene (78% from 3, 73% from 1)
along with some 1,5-difluoro-2,4-dimethoxybenzene (13%
from 3, 15% from 1).46
of the intermediate β-silyl stabilized carbenium ions by water
or alcohols in acetonitrile solutions and isolated in 43−62%
yield after 24−36 h reaction time.48 High yielding Selectfluor-
based fluorodesilylations and fluorocyclizations of allylsilanes
at room temperature have been developed by Gouverneur and
co-workers.49
Only 9−16% of fluorinated product was obtained when
azulene (N = 6.66) and N-fluorocollidinium tetrafluoroborate
(2a-BF4) or N-fluoropyridinium tetrafluoroborate (2b-BF4)
were heated under reflux in acetonitrile for 30−60 min.50a
With Selectfluor (3) as fluorinating reagent conversion of
azulene was complete within 5 min at room temperature, and
34% of 1-fluoroazulene was isolated.50b The low yields were
explained by a competing SET process with formation of
radical species, which initiated polymerization.
Aggarwal and co-workers51 reported the fluorination of
boronate complexes, similar to that depicted in Figure 14,
using Selectfluor (3) in the absence of metal catalysts at low
temperature within 16 h as a method to prepare the
corresponding allyl fluorides. Based on the nucleophilicity of
the boronate complexes determined from the reactions with
benzhydrylium ions and electrophilicities of N−F reagents
obtained in this work, one can conclude that the depicted
boronate complex (N = 8.71) should be fluorinated with any of
the N−F reagents from this study.
Phenylacetylene was reported to be fluorinated by
Selectfluor (3) in refluxing MeCN/H2O mixture within 10−
20 h to give 2,2-difluoro-1-phenylethanone in 36% yield.47 The
fluorination of styrene with 3 in aqueous acetonitrile yielded
48% of the corresponding fluorohydrin at room temperature
(reaction time was not given).16b
The strongest N−F reagent in this study, that is, Selectfluor
(3), was also employed in reactions with allylsilanes, such as
allyltriisopropylsilane (N = 2.04) and allyltriphenylsilane (N =
−0.13). At room temperature, fluorohydrins were formed by
“F+” transfer from 3 to the allylsilanes and subsequent trapping
In accord with the position of 1-(trimethylsiloxy)-
cyclohexene (N = 5.21) at the same level as NFSI (1) in
Figure 14, Differding et al. reported the fluorination of this silyl
enol ether by 1 at room temperature within 24 h in
dichloromethane, which after aqueous workup, yielded 46%
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of 2-fluorocyclohexanone.12 The reaction of 1-
(trimethylsiloxy)cyclohexene with N-fluoropyridinium tetra-
fluoroborate (2b), for which a half reaction time of around 70
h is expected when applying eq 3, was reported to give only
traces of the corresponding fluorinated ketone within 72 h at
room temperature in dichloromethane. Yet, refluxing the
reaction mixture for 6 h resulted in a yield of 41% of 2-
fluorocyclohexanone. The corresponding reaction with 2b-OTf
yielded 87% of fluorinated product within 7 h at room
temperature and the same reactions of the cyclohexanone-
derived silyl enol ether with 2b-BF4 and 2b-OTf in acetonitrile
gave 54% and 83% of 2-fluorocyclohexanone, respectively,
within 15 h at room temperature.14e
A series of ring-substituted acetophenone-derived silyl enol
ethers was efficiently monofluorinated by Selectfluor (3) to
furnish 2-fluoro-1-aryl-ethanones. In accord with the nucleo-
philicity of the parent 1-phenyl-1-(trimethylsiloxy)ethane (N =
6.22), these fluorinations proceeded smoothly at room
temperature in acetonitrile solutions (reaction times not
given)52 and may also be possible with the less reactive
NFSI (1).
α-Fluoro-γ-butyrolactone was obtained in 30−40% yield
through the reaction of 4,5-dihydro-2-(trimethylsiloxy)furan
(N = 12.56) with N-fluorocollidinium triflate (2a) in the
presence of two equivalents of 2,6-di-tert-butylpyridine after 12
h at room temperature.14e Figure 14 suggests that this reaction
should be complete within seconds at room temperature.
In line with Figure 14 and the product studies with enamines
in Table 1, the reaction of Selectfluor 3 (2 equiv) with α-
morpholinostyrene (N = 9.96) gave 74% of difluorinated
acetophenone within 7−8 h at −10 °C.28a According to Figure
14, this reaction should be complete after much shorter
reaction time, and the fluorination of enamines is also possible
with less reactive fluorination reagents (see Table 1).
In accord with their positions in Figure 14, the diethyl 2-
phenylmalonate anion (N = 15.93) and the 2-phenyl
malononitrile anion (N = 15.58) have been reported to be
rapidly fluorinated by NFSI (1)12 and fluorocollidinium salt
2a14e at low to room temperature.
Since published reaction times for synthetic transformations
often do not refer to optimized procedures, the comparison of
predictions by Figure 14 and reported reaction conditions is
not unambiguous. The preceding analysis shows, however, that
all reported fluorination reactions with 1−4 are consistent with
the pattern described in Figure 14: Combination of the
electrophilicity descriptors E determined in this investigation
with the tabulated reactivity parameters N and sN for carbon
nucleophiles can, therefore, be used for the design of further
fluorinations.
Herbert Mayr: 0000-0003-0768-5199
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Professor Helmut Schwarz on the occasion of his
75th birthday. We thank the Deutsche Forschungsgemein-
schaft (SFB 749, Project B1) for financial support.
REFERENCES
■
(1) (a) Cartwright, D. Recent Developments in Fluorine-Containing
Agrochemicals. In Organofluorine Chemistry. Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Taflow, J. C., Eds.; Plenum
Press: New York, 1994; pp 237−262. (b) Lang, R. W. Fluorinated
Agrochemicals. In Chemistry of Organic Fluorine Compounds II;
Hudlicky, M., Pavlath, A. E., Eds; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995; p 1143. (c) Jeschke, P.
ChemBioChem 2004, 5, 570−589. (d) Maienfisch, P.; Hall, R. G.
Chimia 2004, 58, 93−99. (e) Fujiwara, T.; O’Hagan, D. J. Fluorine
Chem. 2014, 167, 16−29.
(2) (a) Elliot, A. J. Fluorinated Pharmaceuticals. In Chemistry of
Organic Fluorine Compounds II; Hudlicky, M., Pavlath, A. E., Eds.;
ACS Monograph 187; American Chemical Society: Washington, DC,
̈
1995; pp 1119−1125. (b) Bohm, H. J.; Banner, D.; Bendels, S.;
Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637−643. (c) Muller, K.; Faeh, C.;
̈
̈
́
́
Diederich, F. Science 2007, 317, 1881−1886. (d) Begue, J. P.;
Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: New York, 2008. (e) Tressaud, A.; Haufe, G. Fluorine and
Health − Molecular Imaging, Biomedical Materials and Pharmaceuticals;
Elsevier: Amsterdam, 2008. (f) Kirk, K. L. Org. Process Res. Dev. 2008,
12, 305−321. (g) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Chem. Soc. Rev. 2008, 37, 320−330. (h) Yerien, D. E.; Bonesi, S.;
Postigo, A. Org. Biomol. Chem. 2016, 14, 8398−8427.
(3) (a) Hung, M. H.; Farnham, W. B.; Feiring, A. E.; Rozen, S.
Functional fluoromonomers and fluoropolymers. In: Fluoropolymers;
Hougham, G., Cassidy, P. E., Johns, K., Davidson, T., Eds.; Plenum
Publishing Co.: New York, 1999. (b) Wei, H. C.; Lagow, R. J. Chem.
Commun. 2000, 21, 2139−2141. (c) Hird, M. Chem. Soc. Rev. 2007,
̈
36, 2070−2095. (d) Kirsch, P.; Binder, W.; Hahn, A.; Jahrling, K.;
Lenges, M.; Lietzau, L.; Maillard, D.; Meyer, V.; Poetsch, E.; Ruhl, A.;
̈
Unger, G.; Frohlich, R. Eur. J. Org. Chem. 2008, 3479−3487.
(4) (a) Olah, G. A.; Shih, J. G.; Prakash, G. K. S. Fluorine-
Containing Reagents in Organic Synthesis. In Fluorine the First
Hundred Years (1886−1986); Banks, R. E., Sharp, D. W. A., Tatlow, J.
C., Eds.; Elsevier Sequoia: New York, 1986. (b) Organofluorine
Chemistry. Principles and Commercial Applications; Banks, R. E., Smart,
B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994. (c) Hiyama,
T. Organofluorine Compounds: Chemistry and Applications; Yamamoto,
H., Ed.; Springer: Berlin, 2000. (d) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, U.K., 2004. (e) O’Hagan, D.
Chem. Soc. Rev. 2008, 37, 308−319. (f) Kirsch, P. Modern
Fluoroorganic Chemistry, 2nd ed.; Wiley-VCH: Weinheim, Germany,
2013. (g) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.
2013, 52, 8214−8264. (h) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr.
Opin. Drug Discovery Dev. 2008, 11, 803−819.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b07147.
■
S
(5) (a) Purrington, S. T.; Kagen, B. S.; Patrick, T. B. Chem. Rev.
1986, 86, 997−1018. (b) Hutchinson, J.; Sandford, G. Elemental
Fluorine in Organic Chemistry. In Organofluorine Chemistry;
Chambers, R. D., Ed.; Topics in Current Chemistry Vol. 193;
Springer: Berlin, 1997; pp 1−43. (c) Sandford, G. J. Fluorine Chem.
2007, 128, 90−104. (d) Rozen, S. Electrophilic Fluorination
Reactions with F2 and some Reagents Directly Derived From It. In
Synthetic Fluorine Chemistry; Olah, G. A., Chambers, R. D., Prakash,
G. K. S., Eds.; Wiley: New York, 1992; pp 143−161. (e) Lagow, R. J.
High-yield reactions of elemental fluorine. In Fluorine The First
Hundred Years (1886−1986); Banks, R. E., Sharp, D. W. A., Tatlow, J.
Details of the product studies, kinetic experiments, and
NMR spectra of all characterized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*herbert.mayr@cup.lmu.de
■
ORCID
Armin R. Ofial: 0000-0002-9600-2793
K
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C., Eds.; Elsevier Sequoia: New York, 1986; pp 321−325. (f) Adcock,
J. L.; Cherry, M. L. Ind. Eng. Chem. Res. 1987, 26, 208−215.
(6) Hiller, A.; Fischer, C.; Jordanova, A.; Patt, J. T.; Steinbach, J.
Appl. Radiat. Isot. 2008, 66, 152−157.
Tetrahedron Lett. 1991, 32, 1779−1782. (d) Davis, F. A.; Zhou, P.;
Murphy, C. K. Tetrahedron Lett. 1993, 34, 3971−3974.
(20) (a) Pereira, R.; Wolstenhulme, J.; Sandford, G.; Claridge, T. D.
̌
W.; Gouverneur, V.; Cvengros, J. Chem. Commun. 2016, 52, 1606−
(7) (a) Tius, M. A. Tetrahedron 1995, 51, 6605−6634. (b) Filler, R.
Isr. J. Chem. 1978, 17, 71−79.
1609. (b) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, J.; Ilupeju, J.;
Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.;
Gouverneur, V. Angew. Chem., Int. Ed. 2013, 52, 9796−9800.
(21) Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lal, G. S. J. Fluorine
Chem. 1992, 59, 157−162.
(8) (a) Hesse, R. H. Isr. J. Chem. 1978, 17, 60−70. (b) Middleton,
W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980, 102, 4845−4846.
(c) Barton, D. H. R.; Ganguly, A. K.; Hesse, R. H.; Loo, S. N.; Pechet,
M. M. Chem. Commun. 1968, 806−808. (d) For a review about
reagents containing the O−F group, see: Rozen, S. Chem. Rev. 1996,
96, 1717−1736.
(9) (a) Lerman, O.; Tor, Y.; Hebel, D.; Rozen, S. J. Org. Chem. 1984,
49, 806−813. (b) Rozen, S.; Lerman, O.; Kol, M.; Hebel, D. J. Org.
Chem. 1985, 50, 4753−4758.
(22) Sudlow, K.; Woolf, A. A. J. Fluorine Chem. 1994, 66, 9−11.
(23) Oliver, E. W.; Evans, D. H. J. Electroanal. Chem. 1999, 474, 1−
8.
(24) Umemoto, T.; Harasawa, K.; Tomizawa, G.; Kawata, K.;
Tomita, K. J. Fluorine Chem. 1991, 53, 369−377.
(25) Toullec, P. Y.; Devillers, I.; Frantz, R.; Togni, A. Helv. Chim.
Acta 2004, 87, 2706−2711.
(10) Rozen, S.; Menahem, Y. J. Fluorine Chem. 1980, 16, 19−31.
(11) Reviews: (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev.
1996, 96, 1737−1756. (b) Taylor, S. D.; Kotoris, C. C.; Hum, G.
Tetrahedron 1999, 55, 12431−12477. (c) Umemoto, T. J. Fluorine
Chem. 2014, 167, 3−15. (d) Baudoux, J.; Cahard, D. Electrophilic
Fluorination With N−F Reagents. In Organic Reactions; Denmark, S.
E., Ed.; Wiley: Hoboken, NJ, 2007; Chapter 2, pp 347−672.
(e) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.;
Paquin, J.-F. Chem. Rev. 2015, 115, 9073−9174.
(26) (a) Xue, X.-S.; Wang, Y.; Li, M.; Cheng, J.-P. J. Org. Chem.
2016, 81, 4280−4289. (b) Li, M.; Zheng, H.; Xue, X.-S.; Cheng, J.-P.
Tetrahedron Lett. 2018, 59, 1278−1285.
(27) (a) For enamines 5a-h see: Timofeeva, D. S.; Mayer, R. J.;
Mayer, P.; Ofial, A. R.; Mayr, H. Chem. - Eur. J. 2018, 24, 5901−5910.
(b) For carbanions 6a,d see: Berger, S. T. A.; Ofial, A. R.; Mayr, H. J.
Am. Chem. Soc. 2007, 129, 9753−9761. (c) For carbanion 6b see:
́
Puente, A.; He, S.; Corral-Bautista, F.; Ofial, A. R.; Mayr, H. Eur. J.
(12) Differding, E.; Ofner, H. Synlett 1991, 187−189.
Org. Chem. 2016, 1841−1848. (d) For the determination of the
nucleophilicity of carbanion 6c see the Supporting Information of this
paper. (e) For carbanion 6e see: Kaumanns, O.; Appel, R.; Lemek,
T.; Seeliger, F.; Mayr, H. J. Org. Chem. 2009, 74, 75−81. (f) For
carbanion 6f see: Corral-Bautista, F.; Mayr, H. Eur. J. Org. Chem.
2013, 4255−4261. (g) For a comprehensive database of nucleophil-
icity parameters N and sN as well as electrophilicity parameters E, see:
http://www.cup.lmu.de/oc/mayr/DBintro.html.
(13) (a) Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452−454.
(b) Davis, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631−1634.
(c) Resnati, G.; Desmarteau, D. D. J. Org. Chem. 1991, 56, 4925−
4929. (d) Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995,
60, 4730−4737. (e) Yasui, H.; Yamamoto, T.; Ishimaru, T.;
Fukuzumi, T.; Tokunaga, E.; Akikazu, K.; Shiro, M.; Shibata, N. J.
Fluorine Chem. 2011, 132, 222−225.
(14) (a) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986, 27,
3271−3274. (b) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron
Lett. 1986, 27, 4465−4468. (c) Umemoto, T.; Tomizawa, G.
Tetrahedron Lett. 1987, 28, 2705−2708. (d) Umemoto, T.;
Tomizawa, G. J. Org. Chem. 1989, 54, 1726−1731. (e) Umemoto,
T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K.
J. Am. Chem. Soc. 1990, 112, 8563−8575. (f) Umemoto, T.;
Tomizawa, G. J. Org. Chem. 1995, 60, 6563−6570. (g) Umemoto,
T.; Nagayoshi, M.; Adachi, K.; Tomizawa, G. J. Org. Chem. 1998, 63,
3379−3385. (h) Kiselyov, A. S. Chem. Soc. Rev. 2005, 34, 1031−1037.
(15) (a) Banks, R. E.; Du Boisson, R. A.; Tsiliopoulos, E. J. Fluorine
Chem. 1986, 32, 461−466. (b) Banks, R. E.; Sharif, I. J. Fluorine Chem.
1991, 55, 207−214.
(28) (a) Peng, W.; Shreeve, J. M. J. Org. Chem. 2005, 70, 5760−
5763. (b) Purrington, S. T.; Jones, W. A. J. Fluorine Chem. 1984, 26,
́
43−46. (c) Diner, P.; Kjærsgaard, A.; Lie, M. A.; Jørgensen, K. A.
Chem. - Eur. J. 2008, 14, 122−127. (d) Nakanishi, S. Steroids 1963, 2,
765−770.
(29) Dilman, D. A.; Belyakov, P. A.; Struchkova, M. I.; Arkhipov, D.
E.; Korlyukov, A. A.; Tartakovsky, V. A. J. Org. Chem. 2010, 75,
5367−5370.
(30) (a) Terrier, F. Modern Nucleophilic Aromatic Substitution;
Wiley-VCH: Weinheim, Germany, 2013. (b) Makosza, M. Nucleo-
philic substitution of hydrogen in electron-deficient arenes. In Arene
Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds;
Mortier, J., Ed.; Wiley: Hoboken, NJ, 2016; pp 269−298.
(c) Makosza, M. Synthesis 2017, 49, 3247−3254. (d) Seeliger, F.;
Błazej, S.; Bernhardt, S.; Makosza, M.; Mayr, H. Chem. - Eur. J. 2008,
14, 6108−6118. (e) Guo, X.; Mayr, H. J. Am. Chem. Soc. 2014, 136,
11499−11512.
(16) (a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.;
Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 595−596. (b) Lal,
G. S. J. Org. Chem. 1993, 58, 2791−2796. (c) Banks, R. E.; Besheesh,
M. K.; Mohialdin-Khaffaf, S. N.; Sharif, I. J. Chem. Soc., Perkin Trans. 1
1996, 2069−2076. (d) Banks, R. E. J. Fluorine Chem. 1998, 87, 1−17.
(31) Gakh, A.; Kiselyov, A. S.; Semenov, V. V. Tetrahedron Lett.
1990, 31, 7379−7382.
(32) Kiselyov, A. S.; Strekowski, L. J. Heterocycl. Chem. 1993, 30,
1361−1364.
(33) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
938−957. (b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.;
Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500−9512. (c) Lucius,
R.; Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91−95.
(d) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−77.
(e) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807−1821.
(f) Mayr, H.; Ofial, A. R. SAR QSAR Environ. Res. 2015, 26, 619−646.
(g) Richter, D.; Hampel, N.; Singer, T.; Ofial, A. R.; Mayr, H. Eur. J.
Org. Chem. 2009, 3203−3211.
(34) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006,
45, 3869−3874.
(35) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165−195.
(36) (a) Differding, E.; Wehrli, M. Tetrahedron Lett. 1991, 32,
3819−3822. (b) Differding, E.; Ruegg, G. M. Tetrahedron Lett. 1991,
̈
32, 3815−3818. (c) Differding, E.; Bersier, P. M. Tetrahedron 1992,
́
(e) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C. H. Angew. Chem., Int. Ed. 2005, 44, 192−212. (f) Singh, R.
P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31−44. (g) Stavber, S.
Molecules 2011, 16, 6432−6464.
(17) Reviews: (a) Muniz, K. Angew. Chem., Int. Ed. 2001, 40, 1653−
̃
1656. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1−PR43.
(c) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47,
1179−1182. (d) Cao, L. L.; Gao, B. L.; Ma, S. T.; Liu, Z. P. Curr. Org.
Chem. 2010, 14, 889−916. (e) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470−477. (f) Lin, J. H.; Xiao, J. C. Tetrahedron
Lett. 2014, 55, 6147−6155.
(18) (a) Cahard, D.; Audouard, C.; Plaquevent, J. C.; Roques, N.
Org. Lett. 2000, 2, 3699−3701. (b) Shibata, N.; Suzuki, E.; Asahi, T.;
Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001−7009. (c) Baudequin,
C.; Loubassou, J. F.; Plaquevent, J. C.; Cahard, D. J. Fluorine Chem.
2003, 122, 189−193.
(19) (a) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29,
6087−6090. (b) Differding, E.; Lang, R. W. Helv. Chim. Acta 1989,
72, 1248−1252. (c) Differding, E.; Ru
̈
egg, G. M.; Lang, R. W.
L
DOI: 10.1021/jacs.8b07147
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Article
48, 1595−1604. (d) Andrieux, C. P.; Differding, E.; Robert, M.;
́
Saveant, J.-M. J. Am. Chem. Soc. 1993, 115, 6592−6599. (e) Vincent,
S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; Wong, C.-H. J. Org.
Chem. 1999, 64, 5264−5279.
(37) Schoeller, W. W.; Niemann, J.; Rademacher, P. J. Chem. Soc.,
Perkin Trans. 2 1988, 369−373.
(38) (a) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. - Eur.
J. 2003, 9, 2209−2218. (b) Ammer, J.; Nolte, C.; Mayr, H. J. Am.
Chem. Soc. 2012, 134, 13902−13911.
(39) (a) Intermediate data of these calculations are given in Table
S71 (Supporting Information). (b) An analogous comparison of ΔGP‡
with ΔGE°T for the fluorinations of five carbanions by N-F reagents 1
and 2a (see Table S72 and Figure S8 of the Supporting Information)
reveals the polar mechanism to be preferred by 72−82 kJ mol−1.
(c) Instead of comparing the Gibbs activation energy for the polar
fluorination (ΔG‡P) with ΔG°ET one might also use the Marcus or
Rehm−Weller relationships to calculate Gibbs energies of activation
for electron transfer ΔG‡ET. Given that both approaches would require
to estimate the intrinsic barriers for electron transfer, we consider the
comparison of ΔG‡P with ΔGE°T (Table 6, Figure 9, and the Supporting
Information) more convincing in cases where ΔG°ET is significantly
larger than ΔG‡P.
(40) (a) Baidya, M.; Kobayashi, S.; Brotzel, F.; Schmidhammer, U.;
Riedle, E.; Mayr, H. Angew. Chem., Int. Ed. 2007, 46, 6176−6179.
(b) Mayr, H.; Ofial, A. R. Acc. Chem. Res. 2016, 49, 952−965.
(41) (a) Linnell, R. H. J. Org. Chem. 1960, 25, 290. (b) Hall, N. F.;
Sprinkle, M. R. J. Am. Chem. Soc. 1932, 54, 3469−3485. (c) Johnson,
C. D.; Katritzky, A. R.; Ridgewell, B. J.; Shakir, N.; White, A. M.
́
Tetrahedron 1965, 21, 1055−1059. (d) Exner, O.; Janak, P. Collect.
Czech. Chem. Commun. 1975, 40, 2510−2523. (e) Meloun, M.;
́
́
Syrovy, T.; Vrana, A. Anal. Chim. Acta 2005, 533, 97−110.
(42) Christe, K. O.; Dixon, D. A. J. Am. Chem. Soc. 1992, 114,
2978−2985.
(43) (a) Marcus, R. A. J. Chem. Phys. 1956, 24, 966−978.
(b) Marcus, R. A. J. Phys. Chem. 1968, 72, 891−899.
(44) Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron 1996, 52, 11341−
11348.
(45) Shamma, T.; Buchholz, H.; Prakash, G. K. S.; Olah, G. A. Isr. J.
Chem. 1999, 39, 207−210.
(46) Stavber, G.; Zupan, M.; Stavber, S. Tetrahedron Lett. 2007, 48,
2671−2673.
(47) Zupan, M.; Iskra, J.; Stavber, S. J. Org. Chem. 1995, 60, 259−
260.
(48) Wang, W.; Xu, B.; Hammond, G. B. Synthesis 2011, 2383−
2386.
(49) (a) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891−
4893. (b) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006, 4,
26−32. (c) Sawicki, M.; Kwok, A.; Tredwell, M.; Gouverneur, V.
Beilstein J. Org. Chem. 2007, 3, No. 34, DOI: 10.1186/1860-5397-3-
34. (d) Wilkinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M.;
Salmon, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2009, 48, 7083−
7086.
(50) (a) Ueno, T.; Toda, H.; Yasunami, M.; Yoshifuji, M. Bull.
Chem. Soc. Jpn. 1996, 69, 1645−1656. (b) Muthyala, R. S.; Liu, R. S.
H. J. Fluorine Chem. 1998, 89, 173−175.
(51) Sandford, C.; Rasappan, R.; Aggarwal, V. K. J. Am. Chem. Soc.
2015, 137, 10100−10103.
(52) Fuglseth, E.; Thvedt, T. H. K.; Møll, M. F.; Hoff, B. H.
Tetrahedron 2008, 64, 7318−7323.
M
DOI: 10.1021/jacs.8b07147
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX