 |
| At Expo Milano 2015, inside the 'Russia World'. Taken by Ed Law. |
In the Como
fluorine conference, I had a stimulating discussion with an insightful
co-worker, who worked in the synthesis of ‘fluorous buckybowls’. He has pointed
me to a great paper by Prof. Mikami et. al. in Chemistry – an European Journal
earlier this year. I have read it and it is impressive – I would love to talk
about that here!
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| Copper Catalyzed coupling reaction of perfluoroalkylzinc reagent. Adapted from [1]. |
Prof. Mikami’s group has reported the synthesis of a
perfluoroalkylzinc reagent, of the structure (RF)2Zn(DMPU)2,
and its application in a copper-catalyzed coupling reaction, that results in
perfluoroalkyl aromatic / heteroaromatic compounds. [1] The zinc reagent
itself, unlike many main group organometallics involving Li and Mg, is a stable
white powder. Yet, as the title of the article has pointed out, it is a
reactive reagent. Like Charlie Bronson, he may have the leisure to play a
harmonica, but he can shoot, too.
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| A trifluoromethylation reaction. Adapted from [2]. |
Some time ago, they have reported a trifluoromethylation
reaction of aromatic halide using a copper catalyst. [2] The perfluoroalkylzinc
reagent is generated in situ from CF3I and zinc dust. In order to
improve the versatility of the methodology, they have then developed the new
reagent, (RF)2Zn(DMPU)2.
 |
| Generation of the stable perfluoroalkylzinc reagent. Adapted from [1]. |
The perfluoroalkylzinc reagent is generated by a reaction
between perfluoroalkyl iodide (RF-I), diethylzinc, and DMPU at -60oC,
using hexane as a solvent. After warming to -20oC and stirring at
this temperature for 48 hours, the reaction mixture is worked up and finally
they afford an air-stable white powder (except when RF = CF3,
which is stable under argon).
The coupling reaction can be done in one-pot. After all the
reactants (perfluoroalkylzinc reagent, copper salt, and aromatic halide /
vinylic halide...) are loaded into the flask at room temperature under argon,
the reaction takes place at elevated temperatures, affording the coupled
product after workup. They have been able to couple 5 different perfluoroalkyl
groups to 2 types of coupling partners – a substituted aromatic halide or a
vinylic halide.
 |
| A selection of achieved chemical products. Adapted from [1]. |
The most important step in the reaction pathway is the transmetallation
of the perfluoroalkyl group, from zinc to copper center. The researchers have
carried out nice 19F NMR experiments to elucidate the possible intermediates,
and these results have proved to show important insights regarding the
reactivity of the different types of perfluoroalkylzinc reagents. Before I go
into these, it would be more logical to look at the observations first.
Though belonging to the fluorine universe, the results in a
trifluoromethyl (CF3) group is rather different from the longer
perfluoroalkyl chains (C2F5, C3F7 ,
C6F13 ...). In most cases, a 10 mol% loading of the
copper catalyst, CuI, is enough to effect the coupling reaction at elevated
temperature, and in some cases even a lower catalyst loading may also work. For
the longer perfluoroalkyl chains, the electronic status of the aromatic
compound (whether it contains an electron withdrawing or electron donating substituent)
is not important, although electron donating groups lead to a longer reaction
time. This is NOT the case for the CF3 group. While aromatic rings
containing electron-withdrawing groups work well, no reaction can be observed
for those substrates with electron-donating groups (methoxy in this case), even
when a stoichiometric amount of CuI is used. When employing 1 eq. of another
copper salt, CuTC, successful reaction
with a good yield can be afforded. This observation indeed confirms what the
researchers have discovered in the 19F NMR experiments. When they mix (CF3)2Zn(DMPU)2
with CuI, they disover 2 singals in the 19F NMR specturm, which correspond to 2
different anionic copper species. When they mix the same zinc reagent with
CuTC, another 2 different signals
appear, and one of them is likely to corresponf to CuCF3. Indeed,
CuCF3 is a likely intermediate in many of the copper-catalyzed
coupling reaction involving trifluoromethyl groups, and these observations may
imply that distinct copper intermediates are involved in all these coupling
reactions.
It can also be seen that, the longer reaction time regarding
the long perfluoroalkyl chains is likely attributed to a slower zinc-to-copper
transmetallation step. And, the temperature range (50-120 oC) also
shows the thermal stability of the perfluoroalkylcopper intermediates in these
reactions.
They have also proposed a possible mechanism.
 |
| Proposed reaction mechanism. Taken from [1]. |
This is an impressive work. In the Como Conference, I have
the great opportunity to meet Professor Kenji Uneyama, who has done a lot of
research on organometallics involving fluorinated compounds. In his wonderful lecture,
he has shown that while a lot of organometallics can be made (Li, Mg, Cu, Zn),
many of them can be rather unstable and can only be used at very low
temperature (including cuprates of the types R2CuLi or R2Cu(CN)Li2).
And, it can be hard to predict (or have strong confidence) which structure will
generate a stable one, you have to experiment on it! I have the impression that
those organometallics involving Cu and Zn tend to be more stable at elevated
temperature, and therefore should find wider applications in coupling
reactions. Given the emergence of many of these great perfluoroalkyl reagents
(see also my recent article ‘The Magnficent ATEbersons’, RFZn(Me)Cl-Li+),
this certainly is a burgeoning field.
By Ed Law
1/9/2015
Reference:
1. Stable but Reactive Perfluoroalkylzinc Reagents: Application
in Ligand-Free Copper-Catalyzed Perfluoroalkylation of Aryl
Iodides
Kohsuke Aikawa, Yuzo Nakamura, Yuki Yokota, Wataru Toya, and
Koichi Mikami
Chem. Eur. J. 2015, 21, 96 – 100
DOI: 10.1002/chem.201405677
2. Y. Nakamura,
M. Fujiu, T. Murase, Y. Itoh, H. Serizawa, K. Aikawa, K. Mikami, Beilstein
J. Org. Chem. 2013, 9, 2404.
Added on 2/9/2015:
I think I have missed a few interesting aspects in
yesterday's article. First, a bit more on the Zinc / copper perfluoroalkyls.
Zinc and copper fluorous organometallics are more thermally stable than their
Li / Mg counterparts, due to a stabilization from a more 'covalent' character
in the metal-carbon bond, which is originated from a softer nature of the
metal. Thus, these compounds tend to be able to survive a higher reaction
temperature.
Second, an observation in the reaction is that, when
electron-donating group substituted aromatic halides are used as reactants, 15%
of pentafluoroethylated by-product can be observed, when 1 eq. of CuTC is used
at 50oC. How does this side product arise? Well, there is evidence
that when trifluoromethylcopper (I), CF3Cu is generated, CF3Cu is in an equilibrium with
[CF2Cu]F-. This can be built up to a longer
perfluoroalkyl copper chain, through a carbene insertion mechanism. This
'oligomerization' can be stopped by adding HMPA. The carbene insertion
equilibrium is the likely reason for the formation of perfluoroethyl
side-products in this coupling reaction, and it has also been observed in other
copper systems. The pentafluoroethyl side-product can be rather difficult to
remove from the crude mixture. As stated, this side-reaction can be
counteracted by adding HMPA (the researchers have used DMPU here instead) or
lower the reaction temperature. Yet, I
suppose 50oC is already the lowest temperature the researchers can
get to, and have ca. 75% isolated yield for the product is already impressive.
by Ed Law
2/9/2015
