Direct preparation of nitriles from carboxylic acids in continuous flow

Article abstract of DOI:10.1021/jo401945r

A continuous-flow protocol for the preparation of organic nitriles from carboxylic acids has been developed. The method is based on the acid-nitrile exchange reaction with acetonitrile, used as the solvent, and takes place without any catalyst or additives under the high-temperature/high-pressure conditions employed. At 350 C and 65 bar, where acetonitrile is in its supercritical state, the transformation of benzoic acid to benzonitrile requires 25 min. The protocol has been tested for a variety of nitriles, including aromatic and aliphatic substrates.

Full text of DOI:10.1021/jo401945r

Note
pubs.acs.org/joc
Direct Preparation of Nitriles from Carboxylic Acids in Continuous
Flow
David Cantillo and C. Oliver Kappe*
Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
S
* Supporting Information
ABSTRACT: A continuous-flow protocol for the preparation of organic
nitriles from carboxylic acids has been developed. The method is based on the
acid−nitrile exchange reaction with acetonitrile, used as the solvent, and takes
place without any catalyst or additives under the high-temperature/high-
pressure conditions employed. At 350 °C and 65 bar, where acetonitrile is in
its supercritical state, the transformation of benzoic acid to benzonitrile
requires 25 min. The protocol has been tested for a variety of nitriles,
including aromatic and aliphatic substrates.
rganic nitriles are an important class of compounds in
organic synthesis, having widespread application as
(20 equiv) of sulfuric acid as an additive and heating for 4−18
h, providing low yields and product mixtures. Aromatic nitriles
decorated with electron-withdrawing groups have also been
prepared by heating the corresponding acid in acetonitrile at
300 °C, without catalyst, in a silver-coated autoclave.14
O
intermediates in the preparation of several other functional
groups1 or heterocycles such as tetrazoles.2 Apart from the
Kolbe nitrile synthesis,3 which refers to the reaction of alkyl
halides with a metal cyanide, the preparation of nitriles from
aldehydes,4 amides,5 or alcohols6 has been described. Usually
these synthetic procedures require two or more reaction steps,
use hazardous reagents, and generate significant amounts of
waste.3−6 Several methods for the synthesis of nitriles from
carboxylic acids have also been reported.7−14 These generally
consist of an amidation process followed by dehydration using
different dehydrating agents such as thionyl chloride7 or
phosphorus compounds.8 Other methods generate the acyl
chloride9 (or fluoride),10 which is treated with a sulfonamide or
azide and subsequently transformed into the nitrile under
thermal conditions.
The above-mentioned drastic conditions required for the
acid−nitrile exchange reaction make this method of little
practical use, especially on a large scale. Scale-up of a reaction
that requires heating of acetonitrile at about 300 °C is
inherently hazardous because of the high vapor pressures
generated by the solvent. Microreactor technology could
potentially overcome this problem, allowing the process to be
performed at very high temperatures and pressures in a safe and
controllable manner,15 even under conditions where acetoni-
trile is in its supercritical state (Tc = 275 °C, Pc = 48 bar).16 In
principle, when an organic solvent in its supercritical state is
used under continuous-flow conditions, improved mass transfer
due to the high diffusivity and improved hydrodynamic
properties due to the very low viscosity of the reaction system
can be expected.17 Moreover, an additional attractive feature of
microreaction technology is the ease with which the reaction
conditions can be scaled through the operation of multiple
systems in parallel (numbering-up, scaling-out), thereby readily
achieving production-scale capabilities.15 In this paper, we
present a continuous-flow synthesis of organic nitriles from
carboxylic acids based on the acid−nitrile exchange reaction
with acetonitrile, which is used as the solvent under
supercritical conditions. No catalyst or other additives are
employed in this high-temperature/pressure (high-T/p)
process, thus simplifying the workup procedure, which simply
consists of evaporation of the solvent and extraction with
aqueous NaHCO3 in cases where not all of the carboxylic acid
is consumed.
The acid−nitrile exchange reaction11 (Scheme 1) is a simple
method for the direct generation of nitriles from carboxylic
Scheme 1
acids that consists of heating the carboxylic acid substrate in the
presence of an organic nitrile (such as acetonitrile) using an
inorganic acid as a catalyst. However, this straightforward
procedure has found little application because of the very high
temperatures required. For example, the preparation of
aliphatic nitriles such as dodecanedinitrile and adiponitrile by
heating the corresponding acids in acetonitrile in an autoclave
at ca. 300 °C have been described.11,12 In both cases, H3PO4
was used as the catalyst although the reaction was observed to
proceed slowly also in the absence of a catalyst. More recently,
the synthesis of several nitriles from carboxylic acids and
acetonitrile at lower temperatures (ca. 95 °C) has been
reported.13 However, this method employed very high amounts
Received: September 3, 2013
Published: September 25, 2013
© 2013 American Chemical Society
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Note
We initiated our investigation by performing some batch
experiments in a sealed microwave vessel using the reaction of
benzoic acid in acetonitrile to generate benzonitrile as a model.
Thus, 2 mL of a 0.5 M solution of benzoic acid in acetonitrile
was heated at 250 °C for 1 h in a single-mode microwave
reactor.18 The pressure generated by the solvent at this
temperature was ca. 31 bar, the limit of the instrument, and
therefore, batch experiments at higher temperatures could not
be performed. HPLC analysis of the resulting mixture revealed
that only ca. 10% of the starting benzoic acid was converted to
benzonitrile. Small amounts of benzamide and N-acetylbenza-
mide, intermediates in the proposed reaction mechanism (see
below), were also detected (1% and 7% yield for benzamide
and N-acetylbenzamide, respectively).
decided to further optimize the reaction parameters at this
temperature. Increasing the residence time from 10 to 25 min
(flow rate = 0.4 mL min−1)21 led to 94% conversion of benzoic
acid to benzonitrile (Figure S3a in the Supporting Informa-
tion). Further increases in the residence time did not
significantly improve the conversion. Because of the acidic
character of the substrate, a bimolecular process where the
carboxylic acid group catalyzes the acid−nitrile exchange
reaction of another benzoic acid molecule could be expected.
In this case, the reactivity would be considerably dependent on
the substrate concentration. However, experiments performed
with variable concentration, keeping all other parameters
constant, revealed that the conversion is independent of the
substrate concentration (Figure S3b).
The relatively low pressure limit of most commercially
available microwave reactors (20−30 bar) makes genuine high-
T/p processing prohibitive.19 However, stainless steel micro-
tubular continuous-flow reactors are capable of readily
achieving temperatures of 350 °C and pressures of 200 bar
(and beyond),20 where acetonitrile is in its supercritical state.
Thus, we decided to move forward with a high-T/p continuous-
flow protocol for the transformation of carboxylic acids to
nitriles using the acid−nitrile exchange reaction with
acetonitrile. Our flow setup (Figure 1 and Figure S1 in the
To demonstrate the general applicability of this continuous-
flow protocol, a series of aromatic and aliphatic carboxylic acids
containing different functionalities, including electron-with-
drawing and electron-donating groups, were transformed into
the corresponding nitriles (Table 1). In all cases, identical
conditions as optimized for benzoic acid (350 °C, 25 min) were
applied. Despite the high temperature employed, the method
displayed a very good compatibility with common functional
groups such as halogen, nitro, alcohol, and ester (Table 1,
entries 2−6). Heteroaromatic compounds such as furan-3-
carboxylic acid (entry 7) and thiophene-2-carboxylic acid (entry
8) as well as several aliphatic carboxylic acids (entries 9−11)
were also successfully converted into the corresponding nitriles.
In most instances, small amounts of unconsumed starting
material were identified after the reaction (Table 1), but
gratifyingly, no other side products or impurities were detected.
The workup procedure thus simply consisted of evaporation of
the acetonitrile under reduced pressure, dilution of the crude
mixture in ethyl acetate or diethyl ether, and extraction of the
unreacted acid with aqueous NaHCO3 (see the Experimental
Section for details). Evaporation of the organic phase under
reduced pressure then furnished the nitrile in good to excellent
yield (Table 1).
A mechanism for the acid−nitrile exchange reaction was
proposed by Becke et al.14 on the basis of experiments with
isotopically labeled acetonitrile. The authors could demonstrate
that during the reaction the carbon atoms of the carboxylic acid
and nitrile moieties are not interchanged, and they proposed a
pathway involving N-acetylbenzamide (B) as an intermediate
(Scheme 2). Hydrolysis of B would generate benzamide C and
release acetic acid as a side product. In the last step,
dehydration of benzamide leads to the nitrile.
To shed further light on the mechanistic proposal and
demonstrate that, as expected, formation of B is the rate-
determining step of the reaction, we decided to perform a series
of microwave batch experiments involving each of the
intermediates. As mentioned above, heating of benzoic acid
in acetonitrile at 250 °C for 1 h gave a mixture containing small
amounts of benzonitrile (10%), N-acetylbenzamide (7%), and
benzamide (1%), while after only 30 min the conversion to
benzonitrile was reduced to ca. 5% (Figure 4 in the Supporting
Information). Notably, heating of N-acylbenzamide B (Scheme
2) in acetonitrile under the same conditions (250 °C, 30 min)
produced a much faster reaction that provided higher amounts
of benzonitrile (53%) and benzamide (10%). Thus, under the
high-T/p reaction conditions used in our protocol, when
benzoic acid reacts with acetonitrile, the N-acetylbenzamide
rapidly evolves to ultimately form benzonitrile. This explains
why no intermediates were observed in the continuous-flow
Figure 1. Schematic diagram of the continuous-flow setup employed
for the preparation of organic nitriles from carboxylic acids.
Supporting Information) consisted of a 60 mL stainless steel
coil (1/8 in. inner diameter) heated in a conventional GC oven
(max. 350 °C). The reaction mixture was pumped through the
reactor with an HPLC pump (0.1−10 mL min−1), and the
pressure of the system was controlled with an adjustable
backpressure regulator set to 65 bar (see Figure S1 in the
Supporting Information).
Conversion of benzoic acid to benzonitrile was again chosen
as the model reaction for the flow optimization. To avoid
problems derived from the high rate of diffusion of the reaction
mixture through the coil in the superheated solvent, we decided
to continuously pump the solution of the substrate in
acetonitrile, collecting samples for analysis when steady-state
conversion was reached. Our first attempts in continuous flow
indicated that very low conversions, comparable to those in the
above-mentioned batch experiments, were achieved at temper-
atures ranging from 250 to 300 °C (see Figure S2 in the
Supporting Information). As the temperature was increased
(keeping the residence time constant), higher conversions were
achieved, and notably, no side products were detected even
when the reaction mixture was heated at 350 °C. Thus, we
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Note
Table 1. Preparation of Organic Nitriles from Carboxylic
Acids and Acetonitrile in Continuous Flow
Scheme 2. Proposed Mechanism for the Acid−Nitrile
Exchange Reaction, Using as a Model the Reaction of
Benzoic Acid with Acetonitrile
a
very high temperatures and pressures not accessible by
conventional sealed-vessel batch reactors and therefore to
minimize the reaction time for a transformation that would
otherwise take exceedingly long periods. At 350 °C, acetonitrile
in its supercritical state reacted with benzoic acid to yield
benzonitrile after only 25 min in a clean reaction. The protocol
was tested for a number of aromatic and aliphatic acids. In all
cases, good to excellent yields were obtained. Moreover, a series
of batch experiments including all of the intermediates involved
in the proposed mechanism for the reaction were performed,
and the results demonstrated the intermediacy of N-
acetylbenzamide and benzamide during the exchange process,
with the initial formation of N-acetylbenzamide being the rate-
determining step.
EXPERIMENTAL SECTION
General Experimental Details. H NMR spectra were recorded
■
1
on a 300 MHz instrument. Chemical shifts (δ) are expressed in parts
per million downfield from TMS as an internal standard. The letters s,
d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet,
and multiplet, respectively. Analytical HPLC analysis was carried out
on a C18 reversed-phase (RP) analytical column (150 mm × 4.6 mm,
particle size 5 mm) at 25 °C using mobile phases A [water/acetonitrile
90:10 (v/v) + 0.1% TFA] and B (MeCN + 0.1% TFA) at a flow rate of
1.0 mL min−1. The following gradient was applied: linear increase from
30% B to 100% B in 8 min, hold at 100% solution B for 2 min. GC/
MS monitoring was based on electron impact ionization (70 eV) using
an HP/5MS column (30 m × 0.250 mm × 0.025 μm). After 1 min at
50 °C, the temperature was increased in 25 °C min−1 steps up to 300
°C and kept at 300 °C for 1 min. The carrier gas was helium and the
flow rate 1.0 mL min−1 in constant-flow mode. HPLC-grade
acetonitrile was used in all of the experiments. Chemicals were
obtained from standard commercial vendors and were used without
any further purification.
a
Conditions: 0.5 M acid in acetonitrile, 350 °C, 0.4 mL min−1 (25 min
b
c
residence time). HPLC conversion (215 nm). Isolated yields from
10 mL (5 mmol) of the crude reaction mixture (see the Experimental
Section for details). Not determined.
All of the compounds synthesized herein are known in the
1
d
literature. Proof of purity and identity was obtained by H NMR and
MS analysis.
General Procedure for the Preparation of Nitriles from
Carboxylic Acids in Continuous Flow. Flow experiments were
performed using a GC oven equipped with a 60 mL stainless steel coil
(1.6 mm inner diameter) and standard HPLC pumps.22 Before use,
the stainless steel coil was subjected to a cleaning and repassivation
procedure (see the Supporting Information). The adjustable back-
pressure regulator (Swagelok) was set to 65 bar. Initially pure
acetonitrile was pumped through the reactor, and after the desired
reaction parameters were achieved (350 °C, 65 bar), the inlet was
switched to a 0.5 M solution of the corresponding substrate in
acetonitrile. Because of the significant solvent expansion produced
under supercritical conditions, careful control of the residence time
was required.21 The residence time was estimated by observing the
total residence time in the reactor (visual inspection) and taking into
reactions performed at 350 °C. Formation of benzonitrile from
benzamide (C) involves dehydration of the amide group, which
requires the presence of a compound that can scavenge water.
In our mechanistic proposal (Scheme 2) the N-acetylbenza-
mide intermediate acts as water scavenger. Indeed, pure
benzamide in acetonitrile at 250 °C was completely unreactive,
while when it was mixed with N-acetylbenzamide, both evolved
to give benzonitrile (see Figure S4).
In summary, we have developed an efficient, catalyst-free
continuous-flow procedure for the direct preparation of organic
nitriles from carboxylic acids and acetonitrile. The capabilities
of the capillary microreactor approach allowed us to work at
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Note
account the volume of the “cold” zones of the reactor (pumps, tubing,
etc.) and the flow rate. After steady state was achieved (ca. 45 min), 10
mL of the crude reaction mixture was collected at the reaction outlet,
and the solvent was gently evaporated under reduced pressure. The
residue was dissolved in ethyl acetate (30 mL) and extracted with a
saturated aqueous solution of NaHCO3 (2 × 10 mL). The organic
phase was then dried over magnesium sulfate and evaporated under
vacuum, yielding the pure nitrile.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.C. thanks the Ministerio de Ciencia e Innovacion
a scholarship.
́
of Spain for
1
Benzonitrile (Table 1, Entry 1). (459 mg, 89%); H NMR (300
MHz, CDCl3) δ 7.69−7.60 (m, 3H), 7.49 (t, J = 12.0 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 132.8, 132.2, 129.1, 118.9, 112.4; MS-EI
m/z 103 (100%), 76 (45%).
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Hz, 1H), 7.34−7.26 (m, 2H), 2.56 (s, 3H); 13C NMR (75 MHz,
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1
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1
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S
* Supporting Information
Supporting figures and copies of 1H NMR spectra of all
prepared compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: oliver.kappe@uni-graz.at.
■
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the solvent is near or in its supercritical state, the solvent expansion
phenomenon is an important factor to be taken into account.
Residence times cannot be directly calculated from the reactor volume
and the nominal pump flow rate, and the actual residence time has to
be manually measured, typically by visual inspection using a colored
substrate. In our case, at a flow rate of 1 mL min−1, a residence time of
10 min was observed, indicating that the solvent expands 6-fold under
the reaction conditions (350 °C, 65 bar). Thus, a flow rate of 0.4 mL
min−1 was required to obtain the desired residence time of 25 min. For
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A. M.; Alanine, A. I. Eur. J. Org. Chem. 2012, 47−52. (b) Cantillo, D.;
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