Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial-F Preference

Article abstract of DOI:10.1002/chem.202001355

Gaining an understanding of the conformational behavior of fluorinated compounds would allow for expansion of the current molecular design toolbox. In order to facilitate drug discovery efforts, a systematic survey of a series of diversely substituted and protected fluorinated piperidine derivatives has been carried out using NMR spectroscopy. Computational investigations reveal that, in addition to established delocalization forces such as charge–dipole interactions and hyperconjugation, solvation and solvent polarity play a major role. This work codifies a new design principle for conformationally rigid molecular scaffolds.

Full text of DOI:10.1002/chem.202001355

Accepted Article
Accepted Article
Title: Understanding the Conformational Behavior of Fluorinated
Piperidines: The Origin of the Axial-F Preference
Authors: Zackaria Nairoukh, Felix Strieth-Kalthoff, Klaus Bergander,
and Frank Glorius
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202001355
Link to VoR: https://doi.org/10.1002/chem.202001355
01/2020

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Understanding the Conformational Behavior of Fluorinated
Piperidines: The Origin of the Axial-F Preference
Zackaria Nairoukh,*† Felix Strieth-Kalthoff,† Klaus Bergander and Frank Glorius*
Dedicated to Prof. Bernd Giese on the occasion of his 80th birthday
Dr. Z Nairoukh, F. Strieth-Kalthoff, Dr. K. Bergander, Prof. Dr. F. Glorius
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany.
E-mail: glorius@uni-muenster.de; z.nairoukh@mail.huji.ac.il
†These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document
Abstract: Gaining an understanding of the conformational behavior
of fluorinated compounds would allow for expansion of the current
molecular design toolbox. In order to facilitate drug discovery efforts,
a systematic survey of a series of diversely substituted and protected
fluorinated piperidine derivatives has been carried out using NMR
spectroscopy. Computational investigations reveal that, in addition to
established delocalization forces such as charge-dipole interactions
and hyperconjugation, solvation and solvent polarity play a major role.
This work codifies a new design principle for conformationally rigid
molecular scaffolds.
The introduction of fluorine atoms into molecules and
materials across many fields of academic and industrial research
is now commonplace, owing to their unique properties and
effects.[1] Therefore, the incorporation of fluorine into drug lead
candidates has been recognized as a powerful strategy to
improve their pharmacokinetic and physicochemical properties.[2]
For example, the high C–F bond energy increases metabolic
stability[2] and the electronic effects of fluorine allow for
modification of critical properties such as the pKa.[2] Significantly,
a fine-tuning of polarity and lipophilicity can increase solubility and
membrane permeability, which may in turn increase the likelihood
of success in clinical trials (Scheme 1).
A particularly striking feature of fluorine substitution is its
impact on the relative orientation of a C–F bond when
incorporated into aliphatic carbocyclic and acyclic systems, which
allows for the design of highly polar compounds.[3] For aliphatic,
heterocyclic systems, these effects can lead to more rigid
structures, which enable the stabilisation of well-defined
conformers. Fluorinated piperidines represent an exceptionally
interesting case for these phenomena, since the piperidine moiety
and related saturated N-containing heterocycles are frequently
present in bioactive compounds.[4] Owing to limited synthetic
access, typically via tedious, multi-step synthesis, the study of
their conformational behavior has been the subject of few reports,
mainly focusing on 3-fluoropiperidine (1) derivatives. For instance,
the axial orientation of fluorine in the protonated 3-
fluoropiperidinium cation was mainly attributed to the occurrence
of strong charge-dipole interactions (C–F···HN+) (Scheme 1A).[5,6]
Scheme 1. The conformational preferences of fluorinated piperidine derivatives
can be attributed to A) charge-dipole interactions, B) hyperconjugation, C)
dipole minimization and D) steric repulsion.
In addition, hyperconjugative interactions, often referred to as the
1
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fluorine gauche effect, can contribute to the stabilisation of the
axial orientation of the fluorine atom, mainly through electron
donation from anti-periplanar C–H bonds into the low-lying σ*C–F
and σ*C–N orbitals (Scheme 1B).[3,7] Additional factors such as
dipole minimization, steric repulsion and solvation effects have
been described to partially contribute to the conformational
behavior, but were considered to be the least competitive
(Schemes 1C–D).[6,8]
While most studies are limited to examples of 3-
fluoropiperidine (1) derivatives, an extensive and systematic
evaluation of the conformational effects of a wide range of
substitution patterns has not been carried out until now. We
believe that such a study would be highly valuable to the scientific
community, in particular since even slight changes in the three-
dimensional structure might dramatically change the likelihood of
success of lead compounds in therapeutic applications.[2]
We recently described a straightforward process for the
preparation of fluorinated piperidines.[9] In this reaction,
fluoropyridine precursors underwent a catalytic dearomatization–
hydrogenation sequence to furnish a plethora of substituted, all-
cis-(multi)fluorinated piperidines in a highly diastereoselective
fashion. Within the course of this study we became interested in
the conformational behavior of the newly accessed fluorinated
piperidines (1–12), obtained as the trifluoroacetamide (1A–12A)
or HCl salts (1B–12B). Analysis of the 3J(19F,1H) coupling in NMR
experiments allowed us to determine the relative orientation of the
fluorine atom(s), which were often found to adopt either axial or
equatorial orientations exclusively.[10] In addition to the TFA and
HCl analogues, we prepared an additional library of unprotected
fluorinated piperidines (NH-analogues, 1C–12C) and studied their
conformational behavior. To rationalize the conformational
behavior of the fluorinated piperidine derivatives (1–12), we
performed a systematic computational analysis (M06-2X/def2-
QZVPP). Individual DFT calculations were performed in the gas
phase and in solution using a polarizable continuum model (PCM,
TFA analogues in CHCl3, HCl- and NH-analogues in water).
Pleasingly, the experimentally observed conformer could be
predicted computationally in almost all cases. For instance, the
free enthalpy differences ΔG between the two conformers in 3-
fluoropiperidine (1) and 3,5-difluoropiperidine (2) derivatives
indicate a strong preference towards the Faxial conformation in
solution (Scheme 2). Interestingly, while the axial preference in
solution for HCl-analogues (1B, 2B) is mainly attributed to
electrostatic interactions (ΔEelect,a-e for 1B and 2B is +12.6,
+14.7 kcal mol-1, respectively), hyperconjugative interactions are
found to play a significant role in TFA- (1A, 2A) and NH-
Scheme 2. The conformational preferences of 3-fluoropiperidine (1) and 3,5-difluoropiperidine (2) and their TFA-(A), HCl-(B), and NH-(C)-analogues. The free
enthalpy differences between the equatorial conformer to the axial conformer (ΔG) are presented as follows: ΔG Solvent (ΔG Gas Phase). The ΔG values for TFA-,
and for both HCl-, and NH-analogues are given in chloroform and water respectively. All values are given in kcal mol-1. Experimentally, all analogues of 1 and 2
showed high axial preference. In NH-analogues 1C and 2C, we were unable to determine the orientation of the N–H bond because of a fast H/D exchange in
solution. aBoth computational analysis and experimental observation were carried out in toluene
2
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Table 1. Conformational behaviour of all-cis-(multi)fluorinated piperidines.[a]
analogues (1C, 2C) (ΔEhyperc,a-e for 1A, 1C, 2A, and 2C is +3.3,
+5.1, +11.7, and +10.8 kcal mol-1, respectively – for more details
see the Supplementary Information). It should be noted that the
axial preference of fluorinated piperidine analogues of 1 and 2
was confirmed experimentally by NMR studies (Scheme 2). Along
these lines, we also performed the same analysis on 3-fluoro-4-
methylpiperidine (3) (Scheme 3). Both computational and
experimental studies showed high axial preference for all variants
(TFA-, HCl-, and NH- analogues). In this particular case, we
believe that in addition to the abovementioned forces (ΔEelect,a-e of
3A, 3B and 3C is –0.8, +8.5, and +13.5 kcal mol-1, respectively;
ΔEhyperc,a-e of 3A, 3B and 3C is +5.0, +3.0, and +5.8 kcal mol-1,
respectively), the steric influence of the methyl substituent (AMe
=
1.7 kcal mol-1) plays a major role in promoting the axial preference
of the fluorine atom (ΔΔEsteric,a-e of 3A, 3B and 3C is +7.5, +6.4,
and +0.3 kcal mol-1, respectively, relative to 1A–C).
Scheme 3. The conformational preferences of cis-3-fluoro-4-methylpiperidine
(3) and its TFA-(A), HCl-(B), and NH-(C)- analogues. All values are given in
kcal mol-1. The experimental observation is based on 3J(19F,1H) values. See the
Supplementary Information for more details.
Inspired by these preliminary results, we conducted the
same systematic analysis for all of the newly accessed fluorinated
piperidine derivatives, including all different analogues (1–12)
(Table 1). The free enthalpy differences (ΔG), electrostatic,
hyperconjugation and steric contributions including dipole
moments and geometries for all conformers are presented in
detail in the Supplementary Information.
[a] The conformational preferences of fluorinated piperidine (1–12) and its R =
TFA-(A), HCl-(B), and NH-(C)- analogues. The ΔG values for TFA- and for both
HCl-, and NH-analogues are given in chloroform and water respectively. All
values are given in kcal mol-1. [b] This compound was measured in toluene.
3
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As mentioned above, in the vast majority of cases the
computed conformer free enthalpy differences in both TFA-, HCl-,
and NH-analogues (in solution) are in qualitative agreement with
the experimentally observed conformational preferences
(Table 1). In a singular event however, the supposedly less stable
conformer, as derived from computational analysis, was observed
experimentally. The free enthalpy difference of 4-
fluoropiperidinium salt (10B) in the gas phase and in aqueous
solution (+3.0, +1.0 kcal mol-1, respectively) suggests that the
axial orientation of the fluorine atom should be more favoured. In
aqueous solution, the equatorial conformer was observed to be
dominant. This puzzling observation suggests that additional
factors might play a major role in predicting the conformational
preference. While examining all computational results, we
realized that that the molecular dipole moment µ has a significant
impact on the stabilisation energy of conformers in polar solution.
In the case of the 4-fluoropiperidinium salt (10B), the equatorial
conformer has a significantly larger dipole moment (µe,gas = 8.0 D)
than the axial conformer (µa,gas = 6.4 D) and can therefore be
significantly stabilized in aqueous solution. Such an effect can be
observed particularly for charged species in highly polar solvents
and is presumably underestimated computationally by the simple
PCM.
Supplementary Information for more details). The computational
analysis however suggests an increasing stability of the more
polar Faxial conformer with increasing solvent polarity (ΔGa-e = +0.2,
+0.5, +0.6, +0.8, and +0.8 kcal mol-1 in C6H6, CHCl3, CH2Cl2,
DMSO and H2O respectively).
To further explore these phenomena, we conducted the
same analysis on 3,5-difluoropiperidine (2), employing different
N-protecting groups (13–15) (Table 2). Initially, we examined the
conformational behavior of the TFA-analogue (2A) in different
solvents and identified the same clear correlation between solvent
polarity and the preference for the Faxial conformation; the higher
the solvent polarity, the higher the preference for axial orientation
(3J(3-Fa,4-Ha) values in C6H6, CHCl3, CH2Cl2, and DMSO are 34.1,
36.1, 38.8, 44.4 Hz respectively). The same observation was
made while studying acetyl-protected 3,5-difluoropiperidine (13):
in both chloroform and DMSO an axial preference was obtained
with significantly higher values of ΔG and 3J(3-Fa,4-Ha) in the
more polar solvent (DMSO). Encouraged by these results, we
considered applying this technique to promote the formation of
the Faxial conformer in further 3,5-difluoropiperidine analogues
(Table 2). Computational investigations in the gas phase, as well
as the experimental observation in chloroform, suggest that in
both Pivaloyl- (Piv) and tert-butoxycarbonyl (Boc)-protected 3,5-
difluoropiperidine (14, 15), the fluorine atoms adopt an equatorial
orientation (3J(3-Fa,4-Ha) = 7.3, 12.5 Hz for 14 and 15
respectively). By increasing the solvent polarity from chloroform
(ε = 4.81) to DMSO (ε = 46.7), the conformational behavior of both
species can be inverted, favoring the Faxial conformation
orientation (3J(3-Fa,4-Ha) = 38.5, 40.4 Hz for 14 and 15
respectively).
Consequently, we became interested in examining whether
solvent polarity can affect conformational behavior, as suggested
by Abraham for the rotamers of ethane derivatives in the 1960s.[11]
We initially investigated whether the axial preference is preserved
in 3,5-difluoropiperidine (2C) in different solvents (See the
Supplementary Information for more details). Both computational
and experimental analyses showed that the fluorine atoms adopt
an exclusively axial orientation in all cases (see the
These results suggest that C–F bonds, although often
considered to be a bioisostere of C–H bonds,[2] can significantly
alter the conformational behavior of fluorinated heterocycles such
as piperidines. To illustrate how this concept could potentially be
applied in the context of molecular design, we investigated the
behavior of 4-methylpiperidine (16) and its fluorinated analogue
cis-3,5-difluoro-trans-4-methylpiperidine (17) computationally
(Scheme 4).
Table 2. The conformational preferences of 3,5-difluoropiperidine derivatives.[a]
Scheme 4. Tuning the conformational behaviour of 4-methylpiperidine
analogues by fluorine substitutions. All free enthalpy values are given in kcal
mol-1.
[a] All values are given in kcal mol-1. The experimental observation is based on
3J(19F,1H) values. See the Supplementary Information for more details.
4
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As expected for the sterically demanding methyl group, the
Meequatorial conformer is preferred in both compounds, both in the
gas phase and in chloroform (Scheme 4). By switching to more
polar solvents such as water, the conformational equilibrium can
be significantly shifted. Whilst compound 16 retains its Meequatorial
conformer in polar solution, the fluorine atoms in 17 induce a
conformational inversion, directing the methyl group into the
sterically hindered axial position – showcasing how fluorine
substitution can be utilized to manipulate the conformational
behavior of polar molecules.[12]
In conclusion, the conformational behavior of fluorinated
piperidines is influenced by the interplay of different forces such
as electrostatic interactions, hyperconjugation and steric factors.
In this communication we provide, for the first time, a detailed and
systematic overview of the major parameters that can control the
conformational behaviour of fluorinated piperidine derivatives
while covering a wide range of substitution patterns on the
piperidine ring. The fluorinated piperidines were analysed
experimentally (through NMR studies) and computationally
(through DFT computations). Interestingly, in addition to the
common forces that contribute to the stabilisation of a specific
conformer, we realized that the dipole moment can be used to
further manipulate the orientation of the fluorine atoms,
particularly in polar solutions. These forces may eventually be
used to fine-tune the conformational structure of lead compounds
which can dramatically affect their likelihood of success in
therapeutic applications.
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Acknowledgements
All computations were carried out on the high-performance
computing system PALMA II (WWU Münster). We thank Prof.
Ryan Gilmour (WWU Münster), Prof. Alexander Hillisch (Bayer
Pharma AG) and Professor Peer Kirsch (Merck KGaA) for helpful
discussions. Financial support by the European Research Council
(ERC Advanced Grant Agreement no. 788558) and Deutsche
Forschungsgemeinschaft (SPP2102) is gratefully acknowledged.
[8]
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[10] It should be noted that the vicinal 3J(19F,1Ha) coupling constants provide
useful insight into the conformational structure, since large values of
3J(19F,1Ha) indicate axial preference and small values of 3J(F,Ha) indicate
equatorial preference (for more details, see Supplementary Section 4,
ref 9).
Keywords: piperidines • fluorine • conformational behavior •
solvation effect • NMR analysis
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5
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Fluorine ax-plained: The axial-F preference of fluorinated piperidines can be attributed to delocalization forces such as charge-
dipole interactions and hyperconjugation. In addition to these established forces, solvation and solvent polarity were found to play a
major role in the stabilization of these entities which was supported by experimental and computational investigations over a variety
of substituted and protected fluorinated piperidine derivatives.
6
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