solid. Despite a few examples,3e,6 the use of solids in flow is
generally avoided, because of pump or reactor clogging.
To address this poor solution stability, we speculated that
transition metal complexes could be produced using flow
chemistry7 whereby soluble ligands are passed through an
insoluble metal source and used immediately in down-
stream reactions (Figure 1). As we demonstrate herein, this
simple idea offers an alternative to glovebox and Schlenk
techniques.
using imidazolidinium salt 1a(Figure 2). Weobservedhigh
yields of NHCꢀCu(I) complexes when an Omnifit column
was packed with 1.65 g of a 1:1 mixture of a solid diluent
and Cu2O (<5 μm particle size). Plugs of pure diluent at
each end of the column were necessary to prevent leaching
of fine-grained Cu2O. Diluents such as silica gel, reverse
phase silica gel, and molecular sieves all prevented fine
Cu2O from leaching out of the column. Molecular sieves
(4 A), however, were optimal as this material not only
filtered fine particles, but also removed water produced
during the reaction.11
Figure 1. Overview for using insoluble metal sources to provide
soluble active metal complexes.
To demonstrate this concept, we investigated the syn-
thesis of N-heterocyclic carbene (NHC)ꢀcopper chloride
complexes8 from insoluble Cu2O and NHC precursors
(Table 1).9 We speculated that using a packed bed
of Cu2O downstream of the pumps would not only allow
for the formation of the desired complex continuously
without clogging, but would also increase the rate
of complex formation due to increased interaction between
solid Cu2O and solute relative to batch conditions. Herein,
we present the use of a packed-bed microreactor to effi-
ciently synthesize known, new, air-sensitive, and chiral
NHCꢀCuCl complexes and illustrate their subsequent
use in downstream reactions.
Figure 2. Effect of temperature on reaction conversion with a
∼2 min residence time.
We employed a Vapourtec R series reactor system10
equipped with a heated tube reactor containing a glass
Omnifit column. Optimization reactions were performed
We measured the conversion of 1a to 2a as a function of
column temperature using a 0.800 mL/min flow rate
(∼2 min residence time; tR). A steep temperature depen-
dence was observed whereby reaction onset began above
60 °C and showed maximum product formation at 110 °C
(Figure 2), resulting in 93% yield of 2a using a 0.800 mL/
min flow rate (Table 1, entry 1).
A 0.800 mL/min flow rate (∼2 min tR) and a 110 °C
column temperature were suitable for most substrates.
Commonly used imidazolium salts, as well as other more
challenging substrates were produced (Table 1). Entries 1
and 2 demonstrate that the flow approach functions well to
make known complexes, and entries 3ꢀ5 represent new or
challenging to produce complexes. For example, 2c de-
monstrates that this method can produce complexes that
under batch conditions produce a cyclic urea product
(Figure 3).9b Next, we turned our attention to demonstrat-
ing that this method is useful for synthesizing new fused
cyclic Cu(I) complexes. For example 2d (Table 1, entry 4)
illustrates that this method can produce other aliphatic
flanked carbenes similar to 2c. Finally, we prepared a
mononuclear Cu(I) complex (Table 1, entry 5) to
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