HCN on Tap: On-Demand Continuous Production of Anhydrous HCN for Organic Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b01941

A continuous process for the on-demand generation, separation, and reaction of hydrogen cyanide (HCN) using membrane separation technology was developed. The inner tube of the reactor is manufactured from a gas-permeable, hydrophobic fluoropolymer (Teflon AF-2400) membrane. HCN is formed from aqueous reagents within the inner tube and then diffuses through the membrane into an outer tubing containing organic solvent. This technique enabled the safe handling of HCN for three different organic transformations without the need for distillation.

Full text of DOI:10.1021/acs.orglett.9b01941

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
HCN on Tap: On-Demand Continuous Production of Anhydrous HCN
for Organic Synthesis
†,‡
Manuel Kockinger, Christopher A. Hone,*,†,‡ and C. Oliver Kappe*,†,‡
̈
†Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE),
Inffeldgasse 13, 8010 Graz, Austria
‡Institute of Chemistry, University of Graz, Heinrichstraße 28, A-8010 Graz, Austria
S
* Supporting Information
ABSTRACT: A continuous process for the on-demand generation, separation, and reaction of hydrogen cyanide (HCN) using
membrane separation technology was developed. The inner tube of the reactor is manufactured from a gas-permeable,
hydrophobic fluoropolymer (Teflon AF-2400) membrane. HCN is formed from aqueous reagents within the inner tube and
then diffuses through the membrane into an outer tubing containing organic solvent. This technique enabled the safe handling
of HCN for three different organic transformations without the need for distillation.
ydrogen cyanide (HCN) is a highly useful and atom-
and dangerous.9 In 1927, Ziegler developed a laboratory scale
method for the isolation of anhydrous HCN from an aqueous
solution of sodium cyanide (NaCN) or potassium cyanide
(KCN) and mineral acid by distillation.10 The method is still
the main approach applied today for preparing anhydrous
HCN on the laboratory scale. Given its potential synthetic
utility, HCN is arguably significantly underutilized in organic
synthesis, which can be attributed to its method of preparation,
high toxicity (LChuman = 150 ppm for 30 min),11 low boiling
point (26 °C), and the possibility of spontaneous exothermic
polymerization.9
H
efficient reagent for organic synthesis.1 HCN is used in a
plethora of synthetic transformations, including the Strecker
reaction for amino acid synthesis,2 transition-metal-catalyzed
cyanation of aryl bromides,3 chain elongation of sugars,4 and
diaminomalonitrile synthesis (Scheme 1).5 The industrial
Scheme 1. Reactions of Hydrogen Cyanide
Consequently, many HCN surrogates have been devel-
oped,12 most notably trimethylsilylcyanide (TMSCN)13 and
acetone cyanohydrin.14 These reagents are easier and safer to
handle than HCN due to their higher boiling point but suffer
from poor atom economy, high cost per mol, high toxicity, and
potentially different reactivity than HCN.15 Another solution is
to liberate HCN in situ from liquid reagents.16 Very recently,
Grundke and Opatz reported a biphasic procedure for the use
of hexacyanoferrates as a nontoxic cyanide source for
conducting Strecker reactions.17 Nonetheless, some reactions
utilizing HCN are highly sensitive to the presence of water;
therefore, the use of an anhydrous HCN source is required. In
addition, there are often compatibility issues between the
HCN-producing and HCN-consuming reactions, thus prevent-
ing a one-pot protocol.
manufacture of HCN is achieved by the Andrussow process,6
the Degussa process,7 or the Sohio acrylonitrile process, where
HCN forms as a byproduct.8 HCN is a bulk chemical
produced in about 1.3 million tonnes per annum (t/a).1 In
contrast with the industrial large-scale production of pure
HCN, its use on the laboratory scale is considered problematic
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01941
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Organic Letters
Letter
Recently, the Skrydstrup group reported the ex situ
generation of anhydrous HCN from KCN and acetic acid
(AcOH) in ethylene glycol within a two-chamber batch system
for use in organic reactions.18 However, the precise control and
range of reaction conditions (temperature, pressure, and
reaction time) are limited compared with conditions that
could be achieved by using continuous-flow technologies.19
The utilization of continuous-flow technology eliminates the
need to store highly reactive and hazardous reagents and
enables them to be prepared on-site and on-demand inside a
closed system with only small quantities generated at any one
time.20 Stevens and coworker reported the in situ formation of
HCN in flow; however, the HCN is generated within the same
tubing as the organic reaction, and thus this protocol relies on
the fact that the organic transformation is compatible with
AcOH and KCN.21 Ley and coworkers pioneered the tube-in-
tube reactor gas-loading concept to enable the safer
introduction of gases into the liquid phase.22 The tube-in-
tube reactor consists of an outer tubing manufactured from
polytetrafluoroethylene (PTFE) and a smaller inner tubing
manufactured from a gas-permeable and hydrophobic fluo-
ropolymer, Teflon AF-2400. The device has been successfully
applied in organic transformations using gases such as H2, CO,
CO2, O3, NH3, and CHF3.22,23 Our group previously reported
the on-demand continuous generation of diazomethane within
the inner tube of the tube-in-tube device by combining a liquid
stream of a Diazald solution with a stream of strong base,
which diffuses through the membrane to be consumed by the
substrate in the outer tube.24 On the basis of our previous
experience with diazomethane, we hypothesized that mem-
brane technology could also be utilized for the on-demand
generation of anhydrous HCN from aqueous reagents.25 The
continuous generation, separation, and reaction of anhydrous
HCN in a controlled manner without the need for distillation
would significantly improve safety. Herein we describe the
development of a safe protocol for the production of
anhydrous HCN and demonstrate the protocol on a number
of important organic transformations.
We commenced our investigation by evaluating the
hydrocyanation of diphenylmethaneimine (1a) as a model
reaction within a tube-in-flask setup (Figure 1 and Figure S1).
The tube-in-flask configuration is particularly appropriate for
organic transformations with long reaction times. Within the
tube-in-flask configuration, the gas-permeable tubing carrying
the aqueous phase for the formation of dissolved gas is coiled
within the flask, and the liquid phase for the organic
transformation is stirred within the flask.26 For the in situ
on-demand generation of HCN, aqueous solutions of 4 M
NaCN and 4 M H2SO4 were continuously pumped into a T-
mixer, and the combined mixture passed through a short PFA
coil before entering the gas-permeable Teflon AF-2400
membrane coil (1.75 mL internal volume). HCN is generated
on the mixing of the two feeds. A back pressure of 2 bar was
applied to the aqueous stream to ensure that generated HCN
remained in solution. The AF-2400 membrane coil was
contained in a 10 mmol stirred solution of 1a (0.2 M in
acetonitrile (MeCN)) within a sealed flask (fill volume = 50
mL and total volume = 100 mL). The outlet aqueous stream
was then neutralized with a saturated solution of sodium
hydroxide (NaOH), which was subsequently quenched with
H2O2. The conversion of 1a was measured by high-
performance liquid chromatography (HPLC) and corrobo-
rated by proton nuclear magnetic resonance (1H NMR) at
Figure 1. (a) Influence of temperature and flow rate on conversion in
the tube-in-flask. (b) Tube-in-flask setup for the hydrocyanation of
diphenylmethanimine (1).
different reaction temperatures and flow rates. The reaction
rate was accelerated at higher temperatures and by using faster
flow rates (Figure 1a). The results clearly demonstrate that
HCN successfully diffuses through the membrane; however,
the relatively slow reaction rate of hydrocyanation resulted in
the accumulation of HCN within the headspace of the flask (as
measured by an HCN detector), particularly at 50 and 70 °C.
By using a 50 μL/min flow rate for each of the aqueous
streams to generate HCN throughout the experiment,
corresponding to ∼10 equiv of HCN, 8.5 h reaction time for
the batch transformation at room temperature provided 2a in
99% isolated yield (2.06 g) after the evaporation of the solvent
(Figure 1b).
We were interested in measuring the HCN yield in the
organic phase within the tube-in-flask system. There is no
established method for determining HCN concentrations
1
within organic solvents, so we selected to compare H NMR
integrals of HCN against 1,2-dichloro-4-nitrobenzene as an
internal standard in MeCN. NMR measurements were
conducted at 10 °C to slow proton-exchange rates. To our
delight, a sharp signal was observed at 4.20 ppm for HCN. By
operating at a combined aqueous flow rate of 200 μL/min, 50
°C reaction temperature, and a residence time of ∼9 min for
the aqueous stream, an HCN yield of 21% was achieved. This
yield corresponds to a throughput of 5 mmol/h. The HCN
yield was decreased to 14% by increasing the combined
aqueous flow rate to 400 μL/min, but throughput was
increased to 6.6 mmol/h.
After the initial proof-of-concept, we turned our attention to
the commercially available tube-in-tube reactor (Scheme 2).27
The utilization of the tube-in-tube reactor ensured that all
HCN remained in solution, with no gas present within the
system. Within this configuration, HCN diffuses from the
aqueous stream within the inner tube through the membrane
into the outer tube containing a stream of the imine derivative
B
DOI: 10.1021/acs.orglett.9b01941
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Organic Letters
Letter
Scheme 2. Continuous Hydrocyanation of
Diphenylmethanimine Derivatives 1a−1d Using a Tube-in-
Tube Reactor
dissolved in MeCN. The streams were successfully heated
above the solvent boiling point by using 2 and 2.7 bar back-
pressure regulators for the inner tube and outer tube,
respectively. The approach prevents potential operator
exposure to HCN during sampling. After the optimization of
reaction parameters, the full conversion of the starting
materials 1a−1d on a 2 mmol scale to the hydrocyanated
analogues 2a−2d was achieved at 110 °C within 15 min of
residence time. This residence time is a significant decrease in
tube-in-flask protocol because higher temperatures can be
applied safely and HCN is not lost to the headspace. Under the
conditions used, 5 equiv of HCN, in theory, could be
generated for each reaction, which could be reduced further to
minimize the amount of HCN and improve the inherent safety.
However, a reduction in HCN equivalents would increase the
residence time and therefore reduce throughput. Thus we
selected 5 equiv as a compromise, a sufficient concentration to
provide a reasonable reaction rate, and a relatively low amount
of HCN formed at any one time to minimize the accumulation
of hazardous HCN. An increase in the impurity formation was
observed at higher temperatures. The derivatives were isolated
with excellent yields (75−91%) after recrystallization from
ethanol (EtOH).
Subsequently, we determined the amount of HCN that
passed through the membrane in relation to the residence time
of the aqueous stream through the tube-in-tube reactor. The
organic stream (MeCN or toluene) was maintained at 15 min
of residence time. NMR measurements were conducted in a
similar manner to the method described above. The internal
standard used was 1,2-dichloro-4-nitrobenzene for MeCN, and
MeCN was the internal standard in the case of toluene as an
organic feed. A positive correlation between the residence time
of the aqueous phase within the inner tube and the HCN yield
in the organic phase was observed (Figure 2a). The yield of
HCN drops from near-quantitative yield within 40 min of
residence time to 47% yield in the case of 10 min of residence
time in MeCN. This HCN yield is a significant improvement
when compared with the tube-in-flask results. In addition,
higher HCN concentrations within the organic phase, albeit at
lower HCN yields, were obtained by applying higher flow rates
for the aqueous streams (Figure 2b). Higher concentrations of
HCN have greater synthetic utility, and thus we decided on a
compromise and used 10 min of residence time for the
Figure 2. Achievable (a) HCN yield and (b) HCN concentration
within organic feed at 50 °C at different aqueous stream residence
times. Residence time of organic feed was 15 min.
aqueous feed for all subsequent reactions (200 μL/min flow
rate of aqueous stream). HCN yields were lower in toluene
than in MeCN. Some organic reactions involving HCN are
sensitive to water; therefore, we assessed the water content
within the organic phase by Fourier-transform infrared
spectroscopy (FTIR) (Figure S6). The level of water detected
in MeCN was <1000 ppm (<0.1 wt %), and the water content
in toluene (PhMe) was below the levels possible for
quantification, thus showing that the organic phase in both
cases can be considered as anhydrous.
The use of the outer tube for performing the organic
transformation in the tube-in-tube reactor has limitations in
terms of feasible reaction times (<1 h) and the fact that the
handling of solids can be challenging (e.g., blockage of the
system from solid formation). Additionally, the inability to
operate the reactor system at low temperatures due to the
freezing of the aqueous stream at 0 °C limits its application,
particularly when considering asymmetric transformations. To
address these challenges, the continuous generation of an
HCN stream within a tube-in-tube reactor to provide “HCN
on tap” to a batch flask, where the HCN was subsequently
consumed in an organic transformation, was envisioned.
Within the tube-in-flask protocol, the HCN is generated inside
the membrane, and the HCN continuously passes through the
membrane into the solution for the duration of the batch
reaction. In contrast, within the “HCN on tap” protocol, the
HCN is generated within a tube-in-tube reactor and passes
through the membrane to a carrier solvent, which is then
added in a semibatch manner to the reaction. The “HCN on
tap” configuration enables the HCN to be introduced in a
controlled manner and at a known HCN concentration. The
versatility of this configuration was demonstrated through its
application to three well-known model transformations that
require the use of anhydrous HCN (Scheme 3).
The enantioselective Strecker reaction catalyzed by chiral
(salen)Al(III) complex 8 requires the use of low temper-
C
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5 mol % diphenyl sulfide as a cocatalyst. DAMN (7) was
isolated in 69% yield, which was comparable to the reported
yield using HCN directly.30
Scheme 3. On-Demand “HCN on Tap” for Synthetically
Important Reactions
In summary, we have developed a protocol for the safe
generation of anhydrous HCN by using membrane technology.
HCN is generated in the inner tube of the tube-in-tube reactor
containing an aqueous stream carrying NaCN and H2SO4.
HCN subsequently diffuses through a gas-permeable mem-
brane into an organic solvent in the outer tube. HCN is a
powerful reagent for organic synthesis, but it has been severely
underutilized in the past due to its low boiling point, toxicity,
and explosiveness. The on-demand generation, separation, and
consumption of this valuable reagent in a commercially
available membrane reactor described herein drastically
improves safety and circumvents the need for distillation.
The described approach avoids the storage, transportation, and
handling of this volatile and toxic compound in large amounts.
The application to useful synthetic transformations for
academic and industrial chemists has been shown. Therefore,
this new approach may allow new synthetic reactions using
HCN to be explored and expand the interest in reactions
utilizing HCN in the future.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01941.
Description and images of the experimental setups,
1
optimization data, and H NMR, 13C NMR, and 19F
NMR spectra of all isolated products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: christopher.hone@rcpe.at.
*E-mail: oliver.kappe@uni-graz.at.
ORCID
atures.28 The stream from the outer tube containing dissolved
HCN (0.3 M in PhMe) was fed directly over 10 min into a
batch flask cooled to −70 °C containing phenylmethanimine
derivative 3 and catalyst. The protocol provided product 4 in
85% yield and 89% ee. This result is similar to the reported
literature yield for the batch protocol from Sigman and
Jacobsen, where product 4 was obtained in 91% yield and 95%
ee.28a The result demonstrates that the “HCN on tap”
approach can be used for the safe preparation of enantiomeri-
cally enriched R-amino-acid derivatives.
The Ni-catalyzed hydrocyanation of olefins is a well-
established transformation and is generally known to require
anhydrous conditions;3 however, the Ni(COD)2 and Xantphos
catalytic system, which was previously developed in the two-
chamber batch system,18 forms a suspension in toluene and
MeCN. Thus this catalytic system cannot be readily performed
within the tube-in-tube system. By using our “HCN on tap”
generator, the hydrocyanation of styrene (5) afforded product
6 in 78% isolated yield.
Christopher A. Hone: 0000-0002-5939-920X
C. Oliver Kappe: 0000-0003-2983-6007
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CCFLOW project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Digital and Economic Affairs (BMDW), and the
State of Styria (Styrian Funding Agency SFG). We thank Joerg
H. Schrittwieser (University of Graz) for performing chiral GC
analysis.
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