10.1002/anie.201813954
Angewandte Chemie International Edition
COMMUNICATION
In general, CF3-fluorination in aliphatic side-chains
increases the hydrophobicity compared to the unsubstituted
analogues Ile and Val. The CF3-substutition in (2S,3S)-5,5,5-
trifluoroisoleucine (5-F3-Ile), however, only marginally alters the
Acknowledgements
We acknowledge D.A. Thomas for proof reading. R.C., J.R., B.K.,
and K.P. thank the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) for support under project id
387284271 – SFB 1349. M.T.B. thanks the Alexander von
Humboldt Foundation and the National Science Foundation
(USA) for support under grant No. CHE-1565941.
overall size (ΩIle = 66 Å2 vs. Ω5-F
= 68 Å2), whereas for
-Ile
3
4,4,4-trifluorovaline (4-F3-Val), an increase of ~ 8–12% in CCS is
observed (ΩVal = 59 Å2 vs. Ω4-F -Val = 64 Å2). Interestingly, the
3
fluorinated diastereomers of 4,4,4-trifluorovaline yield different
hydrophobicity values: The (2S,3S)-4-F3 Val isomer (α = 1.061) is
considerably more hydrophilic than 4-F3-Val(S,R) (α = 1.080), but
both are more hydrophobic than Val (α = 1.053). This observation
is in good agreement with HPLC results[3b] as well as theory,[26]
and indicates that the here-presented approach is sensitive to
small variations within a given structure.
Moreover, a CF2-fluorination leads to a completely different
behavior: 4,4-difluoroaminobutyric acid (4-F2-Abu; α = 1.000)
exhibits a smaller α value than its non-fluorinated analogue (Abu;
α = 1.057). Thus, partial fluorination in aliphatic side-chains can
decrease the overall hydrophobicity of a given amino acid.[25b]
Such prediction upon fluorination is not trivial, but amino acids can
be readily classified using the here-presented approach.
The incorporation of fluorine into phenyl rings exhibits a
different behavior: The H/F substitution reduces hydrophobicity in
the following order: Phe (α = 1.042) > oF-Phe (α = 1.026) >
mF-Phe (α = 1.021) > pF-Phe (α = 1.014) > F5-Phe (α = 0.951).
This rather unusual trend is likely a result of changes in the
electronic structure of the ring. The change of dipole moment
upon fluorination leads to an increase in polarity resulting in more
densely packed clusters. This effect is even more pronounced
when a phosphonate group (R-CF2-PO(OH)2 for p-CF2P-Phe;
α = 0.906) is attached to the phenyl ring (see Phe vs.
Keywords: isotropic growth • gas phase • ion mobility-mass
spectrometry • fluorinated amino acids • hydrophilicity
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driven intermolecular interactions. In order to perform
a
quantitative assessment and classify natural as well as several
non-natural fluorinated amino acids, a correction factor α was
employed, which provides a measure for the deviation from
isotropic cluster growth. The here-presented method represents
a general approach that allows the precise determination of the
intrinsic, unbiased hydrophobicity of amino acids. This approach
not only includes natural building blocks, but also artificial
compounds with complex conditions that make predictions of this
property difficult or impossible. Thus, our method represents a
valuable tool in the context of peptide, protein and drug design.
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