Synthesis, Characterization, and Reactivity of Thermally Stable Anhydrous Quaternary Ammonium Fluorides

Article abstract of DOI:10.1021/acs.orglett.6b03864

The synthesis and properties of a new class of anhydrous quaternary ammonium fluorides, based on the rigid skeleton azabicyclo[2.2.2]octane, is described. Compounds 2a-d were easily prepared by passing the corresponding ammonium iodides over fluoride-based resin followed by drying their hydrated form at 100 or 140 °C under reduced pressure. The stability (experimental and theoretical study), solubility, reactivity, and characterization by solution and solid-state MAS NMR are discussed.

Full text of DOI:10.1021/acs.orglett.6b03864

Letter
pubs.acs.org/OrgLett
Synthesis, Characterization, and Reactivity of Thermally Stable
Anhydrous Quaternary Ammonium Fluorides
Shlomi Elias,* Naama Karton-Lifshin, Lea Yehezkel, Nissan Ashkenazi,* Ishay Columbus,
and Yossi Zafrani*
Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona,74100, Israel
S
* Supporting Information
ABSTRACT: The synthesis and properties of a new class of
anhydrous quaternary ammonium fluorides, based on the rigid
skeleton azabicyclo[2.2.2]octane, is described. Compounds 2a−d
were easily prepared by passing the corresponding ammonium
iodides over fluoride-based resin followed by drying their
hydrated form at 100 or 140 °C under reduced pressure. The
stability (experimental and theoretical study), solubility, reactivity,
and characterization by solution and solid-state MAS NMR are
discussed.
ubstitution of functional groups by a fluoride ion remains a
Scentral tool in the synthesis of compounds containing
fluorine atom/s for various purposes.1 Yet, accomplishing
chemo- and stereoselective transformations under mild con-
ditions is a challenge.2 One way to dramatically enhance the
reactivity of a fluoride ion is to “divest” it from its hydrates and
perform the reaction in an anhydrous aprotic solvent. The term
“naked” fluoride was first introduced by Liotta for the complex
KF/[18]crown-6 in MeCN.3 However, true “naked” fluoride can
only exist in the gas phase, and therefore, the more accepted term
for such a nonhydrated ion is anhydrous fluoride. Indeed, it has
been shown that anhydrous fluoride ions, mainly of tetraalkyl-
ammonium salts, enable fluorination under much milder
conditions than those of their hydrous counterparts.4 However,
these quaternary ammonium compounds when bearing a β
hydrogen atom are unstable and easily undergo a Hofmann
elimination (HE) upon hydrate removal conditions, forming the
−
corresponding trialkylamine, olefin, and bifluoride ion (HF2 ).
For example, upon drying of tetrabutylammonium fluoride
Figure 1. Anhydrous ammonium fluorides.
(TBAF) such decomposition occurs even at rt.5 Therefore,
achieving an anhydrous quaternary ammonium fluoride is a
TMAF.10 Harmon et al. described the synthesis of anhydrous
significant challenge (several approaches including that of the
current work are presented in Figure 1). Christe et al. reported
the first synthesis and characterization of the anhydrous
tetramethylammonium fluoride (TMAF, Figure 1a) and later
described the synthesis of the less stable anhydrous 1-
methylhexamethylenetetramine fluoride, both lacking a β-
hydrogen.6,7 DiMagno et al. reported the in situ preparation of
anhydrous TBAF upon nucleophilic aromatic substitution of
hexafluorobenzene with tetrabutylammonium cyanide (Figure
1b).4 Although unstable, this highly reactive fluoride (anhydrous
TBAF) was successfully used for various synthetic purposes, for
example, the synthesis of fluoropyridines under mild conditions.8
Sanford et al. studied the formation of fluoropyridines using
anhydrous acyl azolium fluoride (Figure 1c)9 and later anhydrous
thermally stable N,N,N-trimethyladamantylammonium fluo-
ride.11 Although this compound contains β-hydrogens, it resists
HE according to Bredt’s rule, as the β-hydrogen is located in
proximity to the bridgehead. However, no properties such as
stability, reactivity, or even solubility were reported.
Following our ongoing studies on the reactivity of fluoride
ions,12 we hypothesized that ammonium fluoride compounds
based on the rigid azabicyclo[2.2.2]octane skeleton would
present relatively high tolerance toward HE (E2 requires
antiperiplanar geometry of the H−C−C−N bonds).13 Herein
Received: December 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03864
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Organic Letters
Letter
we disclose our results on the synthesis (Figure 1d), stability
(using combined theoretical and experimental studies),
solubility, NMR characterization (in both solution and solid
state), and reactivity of such anhydrous ammonium fluorides.
To evaluate this hypothesis, high-level calculations were
performed using the Gaussian 09 program,14 studying the
structure and energetic properties toward HE of these rigid
systems (quinuclidinium 2a and Me-DABCO 2b) vs the flexible
tetraethylammonium fluoride (TEAF, 3). Gas phase geometries
of the initial salt’s ground states, the HE products, and the
corresponding transition states15 were fully optimized at the
B3LYP/6-311G+(d,p) level (Table 1 and Supporting Informa-
tion (SI)).
for all three compounds, albeit, for 2a and 2b the ΔG would be
reduced (6.5 and 10.7 kcal/mol, respectively), relative to 23.4
kcal/mol for 3. To study the energetics also in solution, we used
the IEF-PCM continuum solvation model as embedded in the
G09 package. First, we reoptimized all calculated structures in
acetonitrile (polar) and heptane (nonpolar) at the previous DFT
level of theory using this solvation model. Next, we calculated the
MP2 single-point energies as described above. The nonpolar
solvent heptane exhibited kinetic results which were similar to
those in the gas phase. The free activation energies for 3, 2a, and
2b were calculated to be 21.4, 32.8, and 37.8 kcal/mol,
respectively. On the other hand, in acetonitrile, a much larger
increase in ΔG‡ values was observed (28.3, 43.7, and 46.6 kcal/
mol, respectively), as can be expected.17 Thermodynamic
considerations in solution revealed more marked results. While
3 may undergo a favored HE in both solvents (16.7 kcal/mol in
heptane and 3.5 kcal/mol in acetonitrile), for 2a we found ΔG >
0 in both solvents (0.3 kcal/mol in heptane and 15.3 kcal/mol in
acetonitrile). For 2b we found the elimination to be still favored
in heptane (ΔG = −8.3 kcal/mol) but unfavored (ΔG = 4.6 kcal/
mol) in acetonitrile. Notably, based on frequency calculations at
the DFT level we found that these HE processes are entropy
driven, as may be expected from the dissociation reactions. This
observation is more pronounced for 3 than for 2a−b as ΔS is at
least doubled in the gas phase and solutions. According to these
findings, one may conclude that indeed HE in the bicyclic
systems may be an unfavored process in comparison to other
quaternary ammonium salts such as 3, due to both geometrical
and energetic considerations.
Table 1. Calculated Gas Phase Molecular Structures of 3, 2a,
a
and 2b (GS) and Their Transition States toward HE (TS)
Encouraged by these results, we proceeded to investigate the
synthesis, thermal stability, and characterization of 2a−d as
representatives of a potentially diverse family of compounds. We
started the synthesis with methylation of the commercially
available free amines using iodomethane to obtain ammonium
iodides 1a−d, which were then passed through a column
equipped with an ion-exchanged resin (Amberlite IRA 900 F) to
give the hydrated form of 2a−d quantitatively (Figure 1d). This
procedure avoids the common methods for halide substitution
by a fluoride, using silver fluoride or hydrofluoric acid, which
have their disadvantages. To dehydrate 2a−d, a drying process
that includes three cycles of azeotroping off the water by heating
and reduced pressure (isopropyl alcohol, 2 × 60 °C, 1 × 100 °C,
a
Calculated at B3LYP/6-311G+(d,p) (gray = carbon, blue = nitrogen,
b
c
cyan = fluorine). Dihedral angle. Transition states in kcal/mol.
In all three salts the distance between the quaternary N and F
atom was found to be 2.94−2.99 Å. As expected, each salt possess
H-bonds between the fluoride and three hydrogens (located at
the α methylenes).16 Next, we addressed the ability of these salts
to undergo HE for which an anti conformation between the
nitrogen and the β-hydrogen is essential, i.e. a dihedral angle
(DA) of ca. 180°. While for 3 this conformation is readily
accessible in both the GS and TS, it is clear that a very large
distortion would be necessary in the bicyclic systems 2a and 2b
(Table 1). In fact, the initial angle in the latter compounds was
calculated to be ∼121° (almost 60° smaller than the optimal
angle, and ∼54° smaller than that of 3). Furthermore, these DAs
can be enlarged only by ∼20° in the corresponding transition
states to ∼141°, which is by all means far from ideal. Clearly, HE
in these systems would be energetically costly. Next, we
computed the gas phase energies of this elimination process
for all three compounds using single-point MP2 calculation at the
MP2/6-31G+(d)//B3LYP/6-311G+(d,p) level. The calcula-
tions revealed that, kinetically, there is a much higher activation
barrier for the bicylic systems, as the ΔG‡ for 3 was calculated to
be 22.4 kcal/mol while for 2a and 2b we calculated these values
to be 29.1 and 34.4 kcal/mol, respectively (Table 1).
Thermodynamically, the HE was found to be a favored process
1
oil pump) under inert conditions was performed. H and 19F
NMR analyses in solution showed no decomposition of the
substances up to 100 °C. According to 19F and 13C solid-state
MAS NMR, they exhibited signals that fall relatively close to
those of the related anhydrous TMAF 4 (ca. −85 to −95 ppm,
Figure S1 in SI). We assume that the rigidity of compounds 2a−d
causes broadening of the signals. It should be noted that although
19F solid-state MAS NMR shifts are not a measure for the
“nakedness” of the fluoride ion,18 this analytical technique can
serve as an indication for the dryness, as the chemical shift is
governed by the specified drying state (for 2a, see Figure S2 in
SI). To confirm that 2a−d are in the anhydrous state, they were
subjected to Karl Fischer titrations and showed a water content
of 1.78, 2.04, 8.08, and 2.5 wt %, respectively, values that in all
cases indicate the presence of less than one water molecule per
ammonium salt (A monohydrate should exhibit 11, 11, 9.1, and
7.5 wt % of water, respectively). We concluded that the drying
temperature should be raised. For further stability studies, we
conducted DSC thermal measurements which showed that these
materials are stable up to 160 °C (Figures S3−S7 in SI).
Therefore, we continued to further dry these materials by heating
B
DOI: 10.1021/acs.orglett.6b03864
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Letter
a
Table 2. 19F NMR Chemical Shifts and Solubility (ppm) in Various Solvents
b
c
d
2a
2b
2d
TMAF
TBAF
ACN
−75 (0.09 M)
−71 (0.07 M)
−74 (0.03 M)
−100 (0.08 M)
−116 (0.03 M)
−74 (0.05 M)
−74 (0.07 M)
−73 (0.01 M)
−102 (0.06 M)
−100 (0.02 M)
−150
−74 (0.06 M)
−72 (0.06 M)
−76 (0.05 M)
−100 (0.05 M)
−(0.03 M)
−74
−75
nd
−72
−75
DMSO
e
f
f
DMSO−THF
DCM
nd
g
f
−97
−113
−148
e
nd
g
f
CHCl3
nd
f
MeOH
−150
b
−149
nd
a
c
d
f
Internal standard solutions (0.1 M). Applied for the substance which was dried at 100 °C. Reference 5. Reference 7a. 1:1 mix. Not determined.
Solubility extent in these solvents was determined by the sum of all observed species resulting from a reaction with these solvents.
g
a
them to 140 °C. Compounds 2a and 2d were heated for 11−15 h
Table 3. Reaction of 2a with Benzyl Bromide
1
(oil pump), and according to H and 19F NMR analyses in
solution, no decomposition of these substances was observed.
Karl Fischer titrations showed a water content as low as 0.12 and
0.59 wt %, respectively, and hence these compounds may be
considered as anhydrous. However, 2b and 2c decomposed upon
heating to 140 °C for several hours and, therefore, cannot be
obtained as fully anhydrous compounds at this temperature.19
We assume that in the diazabicyclooctane derivatives 2b,c the
neighboring N atom at the β-position may contribute to this
instability at 140 °C by an anchimeric effect (note that 2c may
first undergo a retro-Menshutkin reaction). Next, we proceeded
to examine the solubility of anhydrous 2a,d and also the dried
compounds 2b,c (less than monohydrate) using α,α,α-
trifluorotoluene as the standard (0.1 M). All four compounds
showed high solubility in methanol, exhibiting a 19F NMR signal
at −150 ppm. It should be noted that, in cases in which an
alcoholic solvent is used to solubilize anhydrous fluoride,
formation of a H-bonded complex 2·(MeOH)n is expected.
Table 2 displays the solubility in ACN, DMSO, the DMSO/THF
mixture (1:1), DCM, CHCl3, and methanol, and the
corresponding chemical shifts. It can be shown that for 2a,b,d
good solubility was observed in these solvents. No solubility was
observed in DMF, THF, chlorobenzene, and less polar solvents.
In some cases the 19F NMR measurements showed an additional
doublet signal at −149 ppm (ACN, DCM, or CHCl3) or −143
b
c
entry equiv of 2a
conditions
conv (%)
100
yield (%)
1
2
3
4
5
1.5
1.5
1.5
1.5
1.5
anhydrous ACN, <2 min
hydrous ACN, 5 days
anhydrous DMSO, <2 min
hydrous DMSO, 7 h
72
79
70
66
66
d
90
100
91
anhydrous DCM, <2 min
100
a
b
1
Anhydrous 2a (0.6 M). Conversion was determined by H NMR.
c
Yield was determined by 19F NMR using 1,3,5-trifluorobenzene as an
d
internal standard. Benzyl alcohol was formed (6%).
conducted in DMSO at 80 °C, and sample aliquots were taken
and quenched by MeOD. The desired product 2-fluoropyridine
was obtained in 68% yield (Table 4, entry 1). In addition, 77%
Table 4. Fluorination of 2-Chloropyridine with 2a
c
d
entry equiv of 2a
conditions
conv (%) yield (%)
a
1
2
3
2
anhydrous DMSO, 4 h, 80 °C
anhydrous DMSO, 2 weeks, rt
93
77
0
68
64
0
b
b
1.2
1.2
−
hydrous DMSO, 2 months, rt
ppm (DMSO) with a J value of 120 Hz that is attributed to HF2
a
b
c
(up to 12%), emphasizing the high basicity of the anhydrous
Anhydrous 2a (0.6 M). Anhydrous 2a (1 M). Conversion was
fluoride specie.6 Interestingly, in both CHCl3 and DCM the
d
determined by H NMR. Yield was determined by 19F NMR using
1
−
1,3,5-trifluorobenzene as an internal standard.
formation of HF2 is accompanied by chlorine−fluorine
exchange (likely, via carbene). However, while the reaction of
2a with CHCl3 is very fast, the related reaction with DCM is
relatively slow, and therefore, the latter solvent can serve as a
suitable medium for fast reactions.
conversion was achieved after stirring the reaction mixture at rt
for 2 weeks using 1.2 equiv of 2a (entry 2). A control reaction
using 2a hydrate in DMSO gave 0% conversion even after two
months, highlighting the significance of maintaining an overall
anhydrous environment (entry 3).
These results demonstrate 2a as a highly reactive yet thermally
stable fluorinating agent which exhibits comparable yields of
fluorination products to the previously reported anhydrous
fluoride materials (TBAF and TMAF).4b,10
It is well-known that anhydrous fluorides can act as strong
bases as we also demonstrated here. Iododecane can serve as a
suitable substrate for studying the products distribution resulting
from the competition between substitution vs elimination. As
expected,4a,21 reaction of this compound with 2a in a DMSO/
THF mixture (1:1) led selectively to the elimination product 1-
decene after <3 min (Table 5, entry 1). A control experiment
using the hydrated 2a gave no selectivity after 48 h (entry 2). Kim
et al. reported that a complex between TBAF and tert-butanol
significantly reduces the basicity of the fluoride ion but increases
its nucleophilicity, and therefore, this compound leads selectively
To explore reactivity, the simplest compound 2a was chosen.
First, we studied the reaction of 1.2−1.5 equiv of 2a, with benzyl
bromide, which allows only a substitution product (but not
elimination). It was found to be almost immediate in anhydrous
ACN, DMSO, and even in the less typical solvent DCM (Table 3,
entries 1, 3, and 5, respectively). Control reactions conducted
under the same conditions using the hydrated 2a in ACN or
DMSO were also performed. Much longer reaction times were
required to achieve full conversion (5 days or 7 h, respectively),
and additionally, the undesired benzyl alcohol byproduct (ca.
6%) was obtained (Table 3, entry 2).
Following these results, we examined the reactivity of 2a
toward a less reactive and more challenging substrate, 2-
chloropyridine. A very common reaction in the chemical
industry is nucleophilic aromatic fluorination for the preparation
of heteroaryl fluorides.20 Alkali metal fluorides (MF) are
generally used, requiring harsh conditions. The reaction was
C
DOI: 10.1021/acs.orglett.6b03864
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Letter
a
Table 5. Substitution vs Elimination of Iododecane Using 2a
ACKNOWLEDGMENTS
This work was internally funded by the Israeli Prime Minister’s
office.
■
b
entry
conditions
SN2:E2
REFERENCES
■
c
d
1
2
3
4
5
anhydrous DMSO−THF, <3 min
1:6.7
(1) (a) See: ChemBioChem. Special Issue: Fluorine in the Life Science
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2720−2725.
c
e
hydrous DMSO−THF, 48 h
anhydrous tert-butanol, 10 days
1:0.6
e
1:0.1
e
hydrous tert-butanol, 6 weeks
1:0
d
anhydrous DCM, 30 min
1:0.6
a
b
c
1
Anhydrous 2a (0.6 M). Ratios were determined by H NMR. 1:1
d
e
mix. Full conversion was obtained. 95% (entry 3) and 42% (entry 4)
conversions were obtained. Starting material and some solvent
impurity were observed (Figures S38 and S40 in the SI).
(5) Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49,
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to the substitution product.22 Inspired by this work, we
proceeded to investigate the reactivity of 2a using anhydrous
tert-butanol as a solvent (but not as a complex). Although much
slower, this reaction led almost exclusively to the substitution
product fluorodecane after 10 days at rt (95% conversion, entry
3). Conducting a control experiment using the hydrated 2a in
tert-butanol under the same conditions gave after 6 weeks
exclusively fluorodecane (entry 4), albeit only 42% conversion
was achieved. Interestingly, when DCM was used, the H-bond
interactions of the anhydrous 2a with the solvent indeed reduced
the basicity of the fluoride ion yielding almost a 2:1 ratio of the
aforementioned products after 0.5 h (entry 5).
(7) Gnann, R. Z.; Wagner, R. I.; Christe, K. O.; Bau, R.; Olah, G. A.;
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(10) Schimler, S. D.; Ryan, S. J.; Bland, D. C.; Anderson, J. E.; Sanford,
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(11) Harmon, K. M.; Southworth, B. A.; Wilson, K. E.; Keefer, P. A. J.
Org. Chem. 1993, 58, 7294−7295.
In summary, this report demonstrates the facile synthesis of a
new family of highly reactive anhydrous ammonium fluorides
and their stability, solubility, and reactivity. The high thermal
stabilities of 2a−d (100 or 140 °C) are attributed to the
distortion formed at the transition state toward HE (DFT
studies). Their solubility in solvents such as CH3CN, DMSO−
THF, and DCM and high reactivity (differences in orders of
magnitude between the anhydrous vs hydrous counterparts)
open the opportunity to accomplish innovative materials (e.g.,
chiral or amphiphilic) that may exhibit excessive potential for
organofluorine chemistry.
(12) (a) Marciano, D.; Columbus, I.; Elias, S.; Goldvaser, M.;
Shoshanim, O.; Ashkenazi, N.; Zafrani, Y. J. Org. Chem. 2012, 77,
10042−10049. (b) Zafrani, Y.; Yehezkel, L.; Goldvaser, M.; Marciano,
D.; Waysbort, D.; Gershonov, E.; Columbus, I. Org. Biomol. Chem. 2011,
9, 8445−8451.
(13) This concept was previously introduced by Harmon et al. who
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their adamantylammonium derivate, no relevant chemical or physical
properties, such as stability, solubility, or reactivity, were reported.
(14) Gaussian 09, Revision B.01; Gaussian Inc.: Wallingford, CT, 2010.
For full citation, see the SI.
(15) All transition states were verified by calculating the intrinsic
reaction coordinates (IRC) and/or by examining the imaginary
frequency’s normal mode. See: Gonzalez, C.; Schlegel, H. B. J. Chem.
Phys. 1989, 90, 2154−2161.
(16) Shirakawa, S.; Liu, S.; Kaneko, S.; Kumatabara, Y.; Fukuda, A.;
Omagari, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2015, 54, 15767−
15770.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03864.
Experimental procedures, analytical data, absolute ener-
gies, number of imaginary frequencies, and Cartesian
coordinates of all stationary points (PDF)
(17) It should be noted that during the course of the reaction including
in the formation of the TS, a considerable decrease in charge is expected.
Therefore, a decrease in the reaction rate is anticipated when the
solvent’s polarity is increased.
(18) Gerken, M.; Boatz, J. A.; Kornath, A.; Haiges, R.; Schneider, S.;
Schroer, T.; Christe, K. O. J. Fluorine Chem. 2002, 116, 49−58.
(19) This observation does not contradict the DSC results, as these
compounds were heated in this case for much longer periods.
(20) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225.
(21) Schwesinger, R.; Link, R.; Wenzl, P.; Kossek, S. Chem. - Eur. J.
2006, 12, 438−445.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yossiz@iibr.gov.il.
*E-mail: nissan.ashkenazi@iibr.gov.il.
*E-mail: shlomie@iibr.gov.il.
(22) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.;
Katzenellenbogen, J. A.; Chi, D. Y. J. Org. Chem. 2008, 73, 957−962.
ORCID
Ishay Columbus: 0000-0001-6620-6966
Yossi Zafrani: 0000-0001-5977-528X
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.6b03864
Org. Lett. XXXX, XXX, XXX−XXX