Mechanistic Study of Ru-NHC-Catalyzed Hydrodefluorination of Fluoropyridines: The Influence of the NHC on the Regioselectivity of C–F Activation and Chemoselectivity of C–F versus C–H Bond Cleavage

We describe a combined experimental
and computational study into
the scope, regioselectivity, and mechanism of the catalytic hydrodefluorination
(HDF) of fluoropyridines, C5F5–xHxN (x = 0–2),
at two Ru­(NHC)­(PPh3)2(CO)­H2 catalysts
(NHC = IPr, 1, and IMes, 2). The regioselectivity
and extent of HDF is significantly dependent on the nature of the
NHC: with 1 HDF of C5F5N is favored
at the ortho-position and gives 2,3,4,5-C5F4HN as the major product. This reacts on to 3,4,5-C5F3H2N and 2,3,5-C5F3H2N, and the latter can also undergo further HDF to 3,5-C5F2H3N and 2,5-C5F2H3N. para-HDF of C5F5N is also seen and gives 2,3,5,6-C5F4HN as
a minor product, which is then inert to further reaction. In contrast,
with 2, para-HDF of C5F5N is preferred, and moreover, the 2,3,5,6-C5F4HN regioisomer undergoes C–H bond activation to form
the catalytically inactive 16e Ru-fluoropyridyl complex Ru­(IMes)­(PPh3)­(CO)­(4-C5F4N)­H, 3. Density
functional theory calculations rationalize the different regioselectivity
of HDF of C5F5N at 1 and 2 in terms of a change in the pathway that is operating with
these two catalysts. With 1, a stepwise mechanism is
favored in which a N → Ru σ-interaction stabilizes the
key C–F bond cleavage along the ortho-HDF
pathway. With 2, a concerted pathway favoring para-HDF is more accessible. The calculations show the barriers
increase for the subsequent HDF of the lower fluorinated substrates,
and they also correctly identify the most reactive C–F bonds.
A mechanism for the formation of 3 is also defined, but
the competition between C–H bond activation and HDF of 2,3,5,6-C5F4HN at 2 (which favors C–H
activation experimentally) is not reproduced. In general, the calculations
appear to overestimate the HDF reactivity of 2,3,5,6-C5F4HN at both catalysts 1 and 2.