A halogen bond-donor amino acid for organocatalysis in water

Article abstract of DOI:10.1039/C8CC06010J

Herein we report a halogen bond-donor amino acid, 4-iodotetrafluorophenylalanine, which behaves as a catalyst for the aqueous synthesis of bis-(heterocyclic)methanes. We also provide experimental evidence that halogen bonding is a plausible explanation fo

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Reactivity differences of Sc
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A Halogen Bond-Donor Amino Acid for Organocatalysis in Water
a
a
a
a
Greta Bergamaschi,* Luisa Lascialfari, Andrea Pizzi, Maria Isabel Martinez Espinoza, Nicola
b
a
c
a
Received 00th January 20xx,
Accepted 00th January 20xx
Demitri, Alberto Milani, Alessandro Gori,* and Pierangelo Metrangolo
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein we report
a
halogen bond-donor amino acid, 4-
iodotetrafluorophenylalanine, which behaves as catalyst for the
aqueous synthesis of bis-(heterocyclic)methanes. We also provide
experimental evidence that halogen bonding is a plausible
explanation for the observed catalytic effect.
A halogen bond (XB) is the noncovalent interaction between
an electrophilic halogen atom acting as a Lewis acid (XB-donor)
and a nucleophilic species behaving as a Lewis base (XB-
1
Fig. 1 a) Chemical structure of F(F4I); b) Plot of the MEP computed by means of DFT
calculations on the 0.001 a.u. contour of the isodensity surface (see S.8 for
computational details). Colour ranges adopted in the map are (in kcal/mol): red, lower
than -18.8; yellow -6.3; green 0.0; light blue +6.3; blue, larger than +25.1.
acceptor). The XB has been exploited for many applications,
with a particular emphasis on crystal engineering and XB-
2
driven assembly of supramolecular structures. The use of XB
in organocatalysis is also rapidly growing and, in this frame, it
is remarkable that XB was recently rationalized as the origin of
molecular iodine catalytic activity in certain organic
transformations (e.g., Michael addition, Friedel−Craꢀs
catalysis in aqueous media. Consequently, we focused our
attention on the unnatural XB-donor amino acid 2,3,5,6-
4
tetrafluoro-4-iodophenylalanine F(F I), (Fig. 1a), for which the
3
synthesis of the corresponding Fmoc-protected analogue was
6
previously described. In our hands, obtaining large amounts
reaction, etc.). Yet, XB-based catalysis remains a largely
unexplored topic.
of the latter by means of the reported multistep procedure
proved to be a laborious and time-consuming task. Therefore,
we designed a new and straightforward synthetic strategy that
Recent examples reported on the use of positively charged
or neutral XB-donor catalysts for the electrophilic activation of
4
,5
substrates in
a plethora of organic transformations.
4
provided us with the unprotected F(F I) amino acid, as
However, to the best of our knowledge, catalyst application
was limited to reactions in organic solvents. This is probably
due to the scarce aqueous solubility of common XB-donor
trifluoroacetate (TFA) salt, in gram-scale and good yields (32%
overall). To this end, it was key for the new procedure to
consistently reduce the number of synthetic steps down to six
scaffolds,
typically
containing
iodopolyfluoroaromatic
(
see Scheme S1).
moieties. The development of more water soluble catalysts
may therefore open up new perspectives in the field of XB-
driven organocatalysis. In this context, we envisioned that by
introducing the 4-iodo-2,3,5,6-tetrafluorophenyl moiety in an
amino acid scaffold, we would have preserved its XB-donor
properties while imparting a sufficient water solubility to allow
The computed molecular electrostatic potential (MEP) of
4
F(F I) shows the existence of a relevant σ-hole (Fig. 1b) with a
MEP value of 128 kJ/mol along the extension of the C-I bond,
7
which is comparable to values reported in the literature. This
was also confirmed by the single-crystal X-ray structure of
F(F
a chiral monoclinic unit cell (P2
amino acid molecules in the asymmetric unit. Its crystal
structure clearly shows the ability of F(F I) to form a strong
4
I), after it crystallized from a 1:1 water/acetone mixture in
1
space group), with three
4
halogen bond with a very short I···O contact (2.82(2) Å, Fig. 2,
inset) between the iodine atom and the carbonyl oxygen of an
adjacent molecule (C-I···O angle: 167.0(5)°). XB occurs almost
orthogonally to the hydrogen bonding involving the same
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Fig. 3 Conversion vs. time curves for the benchmark reaction performed at 60 °C and linear
fits for the determination of initial slopes. krel are relative to the non-catalyzed reactions.
Fig.
2 Possible carbonyl-catalyst interactions. For the sake of simplicity, only
interactions involving aldehydes are depicted, but those involving 4-hydroxycoumarine
are not excluded: Left, formation of a genuine XB between carbonyl oxygen and
slope of conversion versus time, we could estimate that the
polarized iodine of F(F
4
I) or, right, water mediated XB. Inset: Partial crystal structure of
4
F(F I) relative reaction rate constant (krel) is about 3-fold
4
F(F I) showing the halogen bond involving the iodine atom and the carbonyl oxygen of
a nearby amino acid molecule (colour code: Carbon: grey; iodine: purple; fluorine: light higher than that of the uncatalyzed reaction (Fig. 3).
green; oxygen: red; hydrogen: white).
Similar results were obtained in the presence of the amine-
4
protected derivative Fmoc-F(F I), thus excluding the possible
+
carbonyl oxygen with the NH3 group of an adjacent molecule
involvement of the zwitterionic ammonium moiety in the
catalysis (Table S2 and Fig. S2). It should be noted that
tyrosine, despite being a good hydrogen bond-donor, is only
poorly activating the substrate, suggesting that halogen
bonding is more effective in water than hydrogen bonding
(
angle I···O···N of 106.7(7)°, see S.I. for details).
Given the outstanding XB-donor properties of F(F4I), we
moved to explore its possible XB-mediated catalytic
applications in water taking as a model reaction the synthesis
of bis-(heterocyclic)methanes, using benzaldehyde and 4-
10
because of its stronger hydrophobicity. Furthermore, the fact
8
hydroxycoumarine as substrates. Previous literature reported
9
this reaction to proceed spontaneously at 100 °C in 5 hours.
that TFA salts of Br-Phe, Tyr, and F(F
activities, allows to exclude a major role of acid traces in the
catalysis. Overall, these results support plausible
4
I), show quite different
However, we could immediately assess that the addition of
a
0
.2% F(F4I) in the reaction mixture, considerably increased the
involvement of XB in the reaction activation mechanism.
We then additionally tested a number of aromatic
aldehydes differing for the presence of electron-withdrawing
rate of product formation (> 97% in 20 minutes, Table S1,
entry 1). Remarkably, the presence of 0.2% F(F4I) significantly
improved product formation also at a lower temperature (97
(EWG) and electron-donating (EDG) groups at the para
%
in 1h, 60°C).
position of the phenyl ring (Table 3). As expected, the nature
of the aromatic substituents on aldehyde substrates
significantly impacted these catalyzed reactions, with more
electrophilic aldehydes being the most reactive. Interestingly,
this trend was not observed in the absence of the catalyst, i.e.,
the spontaneous reaction (see Table S3).
In order to consolidate our initial hypothesis on the
possible role of XB in promoting a catalytic interaction with the
substrates, we screened differently polarized halogenated
phenylalanines to assess whether weakening or eliminating
the XB-donor properties of the catalyst may alter the reaction
kinetics. To this end, we used L-phenylalanine (Phe),
In order to further establish the occurrence of an
interaction between the substrates and the catalyst, we
pentafluoro-L-phenylalanine
(F
5
-Phe),
and
4-bromo-L-
phenylalanine (Br-Phe) for their absent/poor XB-donor
propensity, respectively, while 4-iodo-L-phenylalanine (I-Phe)
was expected to maintain a certain catalytic activity despite it
lacks the polyfluorinated aromatic substitution that
exacerbates the iodine atom polarizability. Finally, tyrosine
moved to spectroscopic analyses (NMR, ATR-FTIR), DSC, and
19
single-crystal X-ray diffraction experiments.
F-NMR
spectroscopy experiments demonstrated that in the reaction
conditions, F(F I) fluorine atoms in ortho positions to the C-I
4
fragment undergo a 0.85 ppm up-field shift (Fig. S1), which is
1a
typical of the C–I fragment involvement in XB. Unfortunately,
(Tyr) was used as a hydrogen bond (HB)-donor catalyst to
compare HB with XB in the same experimental set-up. We set
conditions for comparison at 60 °C and evaluated catalyst
efficiencies by calculating initial rates (slopes) in the linear
traits of reaction curves. With respect to spontaneous
reaction, no significant acceleration rate was detected in the
4
all attempts to obtain 1:1 F(F I) co-crystals with the starting
substrates were unsuccessful. However, this was not totally
unexpected, since dimeric halogen-bonded complexes have
usually low melting points and the formation of stable co-
11
crystals may prove challenging. For this reason, we turned
presence of Phe, F
of I-Phe, iodine, and F(F
product formation, instead. By linear regression of the initial
5
-Phe, and Br-Phe. Consistently, the addition
our attention to co-crystallize N,N-dimethyl amino
benzaldehyde (1b) with 1,4-diiodotetrafluorobenzene (1,4-
4
I) considerably increased the rate of
2
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In conclusion, in the present work we explored the
possibility to perform XB-promoted catalysis in water by
4
exploiting an XB-donor amino acid F(F I) that combines
excellent XB-donor properties with good water solubility. To
the best of our knowledge, this is the first case of XB-catalyzed
reaction in water involving an amino acid, paving the way
towards a new broader and more sustainable perspective in
XB-promoted catalysis applications. Moreover, the amino acid
Fig. 4 XBs in the co-crystal formed between 1,4-DITFB and 1b. Halogen bond
occurs orthogonally to the carbonyl oxygen with an angle I2···O1···C7 of 113.6(2)°
and I1···O2···C28 of 107.6(3)°. Carbon: grey and green; iodine: purple; fluorine:
yellow; oxygen: red; hydrogen: light grey.
4
F(F I) is a new and powerful building block for the
straightforward incorporation of the catalytic tetrafluoroiodo
moiety into higher complexity structures, such as peptide-
based scaffolds.
DITFB), a very well-known and strong ditopic XB-donor, as
a model of the iodine-carbonyl interaction. Single crystals were
obtained from 1:1 chloroform solution after evaporating the
solvent in three days. The asymmetric unit consists of two
aldehyde molecules and two 1,4-DITFB units. Both XB-donor
modules form XBs with the carbonyl oxygen atoms of 1b. The
C-I···O synthon drives the self-assembly of a supramolecular
trimer (Fig. 4); both XB-donor modules form short XBs with the
carbonyl oxygens of 1b (Fig. S11). It is worth underlining that
aldehyde 1b is the less activated substrate towards the
condensation with 4-hydroxycoumarine. Here, it is easy to
appreciate the key role of XB in lowering the electron density
on the aldehyde carbon, hence activating also a substrate that
is very less prone to react without catalyst (see Table S3). It is
also noteworthy that the iodine atoms of 1,4-DITFB are
actually less pronounced XB-donor groups compared to the
This work was partially supported by the European
Research Council (ERC) through the grant FOLDHALO (no.
3
07108). CARIPLO foundation is also gratefully acknowledged
for partial financial support (grants no.s 2014−0746 and 2016-
472).
0
Conflicts of interest
There are no conflicts of interest to declare.
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1
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1
3
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