DOI: 10.1002/chem.201402520
Communication
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Microreactors
Extremely Fast Gas/Liquid Reactions in Flow Microreactors:
Carboxylation of Short-Lived Organolithiums
Aiichiro Nagaki, Yusuke Takahashi, and Jun-ichi Yoshida*[a]
The second one is the issue of chemistry. The reaction with
Abstract: Carboxylation of short-lived organolithiums
CO2 should be faster than that with an electrophilic functional
bearing electrophilic functional groups such as nitro,
group in the organolithium species, although the rate depends
cyano, and alkoxycarbonyl groups with CO2 to give car-
on the concentration of CO2 in the solution. The question is
boxylic acids and active esters was accomplished in a flow
what kind of electrophilic functional groups are compatible
microreactor system. The successful reactions indicate that
with the carboxylation. Here, we show that these hurdles were
gas/liquid mass transfer and the subsequent chemical re-
overcome using the flow microreactor system and that aromat-
action with CO2 are extremely fast.
ic carboxylic acids bearing electrophilic functional groups were
synthesized from the corresponding aromatic halides.
The reactions were carried out using a flow microreactor
Carboxylic acids and their derivatives are important classes of
compounds in organic chemistry. Although various methods
for synthesis of carboxylic acids have been used so far, carbox-
ylation using CO2 gas as a carbon feedstock[1] is useful and at-
tractive from an environmental point of view.[2] Despite recent
remarkable advances in this field,[3] classical carboxylation of
organometallics with CO2 still serves as a powerful method be-
cause of efficiency and convenience.[4] However, the method
suffers from the problem of incompatibility of electrophilic
functional groups such as nitro, cyano, and carbonyl groups,
which causes severe limitations in the synthesis of carboxylic
acids and their derivatives having a variety of functions and
biological activities.
system composed of three T-shaped micromixers (M1, M2, and
M3) and three microtube reactors (R1, R2, and R3) as shown in
Figure 1. An aryl halide and nBuLi or PhLi were mixed in M1
Recently, we have reported that various short-lived highly
unstable organolithiums such as aryllithiums bearing electro-
philic functional groups could be generated and used for reac-
tions with subsequently added electrophiles before they de-
compose[5] by taking advantages extremely short residence
times, which is one of the characteristic features of flow micro-
reactors.[6–8]
Figure 1. A flow microreactor system for the reactions of organolithiums
with CO2 gas. T-shaped micromixers: M1, M2, M3; microtube reactors: R1,
R2, R3; flow controller: FC; pressure gage: P.
and the halogen/lithium exchange was carried out in R1 to
generate the corresponding aryllithium. In the next step, CO2
gas (1.5 equiv) that was pressurized to 3.0 bar with a gas pres-
sure regulator valve was introduced at M2 using a flow con-
troller, and the carboxylation was carried out in R2. In the last
step the reaction was quenched by MeOH at M3 and R3.
The carboxylation of p-nitrophenyllithium[11] was first exam-
ined. The iodine/lithium exchange reaction was carried out
with the residence time of 0.014 s at À208C. In the previous
work,[11] we have already revealed that p-nitrophenyllithium
can be effectively generated under these conditions. We have
also revealed that p-nitrophenyllithium decomposes with the
residence time longer than ca. 0.4 s at À208C. As shown in
Table 1, the corresponding carboxylic acid was obtained in
78% yield. This means gas/liquid mass transfer and the chemi-
cal reaction of p-nitrophenyllithium with CO2 are much faster
than its decomposition. Under similar conditions m- and o-ni-
trophenyllithiums were carboxylated effectively. The carboxyla-
There are two hurdles that we expected in the implementa-
tion of CO2 as an electrophile in the reactions of short-lived or-
ganolithium species; the mass transfer between the CO2 gas
phase and the solution phase and the rate of the chemical re-
action of organolithium species with dissolved CO2. The first
one seems to be mainly the issue of fluidics although the mass
transfer rate also depends on the nature of the gas and that of
the solution. It is well known that the use of flow microreactors
enables fast mass transfer in gas–liquid biphasic reactions.[9,10]
[a] Dr. A. Nagaki, Y. Takahashi, Prof. J.-i. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering, Kyoto University Nishikyo-ku
Kyoto, 615-8510 (Japan)
Fax: (+81)75-383-2727
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402520.
Chem. Eur. J. 2014, 20, 1 – 5
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