Continuous hydroamination in a liquid-liquid two-phase system.

Article abstract of DOI:10.1039/b111630d

The direct addition of NH across a CC multiple bond (hydroamination) was efficiently catalysed in a liquid-liquid two-phase system. The latter comprised a polar catalyst phase of Zn(CF3SO3)2 in the ionic liquid 1-ethyl-3-methylimidazolium trifuoromethanesulfonate and a substrate mixture in heptane. The possibility of catalysing different hydroamination reactions continuously was demonstrated.

Full text of DOI:10.1039/b111630d

Continuous hydroamination in a liquid–liquid two-phase system†
Volker Neff, Thomas E. Müller* and Johannes A. Lercher
Lehrstuhl für Technische Chemie II, Technische Universität München, Lichtenbergstraße 4, 85747 Garching,
Germany. E-mail: Thomas.Mueller@ch.tum.de; Fax: +49 89 28913544; Tel: +49 89 28913538
Received (in Cambridge, UK) 21st December 2001, Accepted 8th March 2002
First published as an Advance Article on the web 26th March 2002
The direct addition of NH across a CC multiple bond
(hydroamination) was efficiently catalysed in a liquid–liquid
two-phase system. The latter comprised a polar catalyst
phase of Zn(CF3SO3)2 in the ionic liquid 1-ethyl-3-methyl-
imidazolium trifluoromethanesulfonate and a substrate
mixture in heptane. The possibility of catalysing different
hydroamination reactions continuously was demonstrated.
polar heptane minimises leaching of zinc into the product
phase.
To test the scope and suitability of two-phase catalysis, three
model reactions were explored (eqn. 1–3). The reactions were
performed in the batch mode and the mixtures stirred suffi-
ciently fast to obtain a homogeneous suspension of the two
phases. In this case, a large surface area was achieved, enabling
fast mass transfer across the phase boundary.
The direct reaction of alkenes and alkynes with N–H bonds
(hydroamination) is a highly attractive route for the synthesis of
nitrogen containing compounds.1 Currently, several research
groups compete to find new and more efficient catalyst systems
for this type of reaction. Recently, late transition metals
complexes,2,3 such as [Pd(Triphos)](CF3SO3)2, where Triphos
(1)
(2)
=
bis(2-diphenylphosphinoethyl)phenylphosphane, were
found to be effective homogeneous catalysts. Late transition
metal catalysts can be immobilised on a solid support.4 The
possibility of catalysing hydroamination reactions with such
catalysts has been demonstrated for Zn2+ ion exchanged zeolites
in the addition of methylamine to propyne and the cyclisation of
6-aminohex-1-yne.5 However, neither the homogeneous nor the
heterogeneous catalysts have a sufficient activity and stability
for a commercial process.
One strategy to achieve higher reaction rates is the use of a
high concentration of catalyst, coupled with an efficient
separation. This can be realised in liquid–liquid two-phase
systems. So far, only one example of hydroamination in a two-
phase system has been realised. In the special case of cyclising
o-ethynylanilines to indoles, the two-phase system comprises a
solution of palladium(II)-salts in CH2Cl2 and aqueous HCl.6 The
challenge was to develop a new two-phase system, which would
allow hydroamination reactions to be performed in a more
general manner.
The choice of the solvent pair faces a number of boundary
conditions: (i) Most late transition metal catalysts for hydro-
amination reactions are cationic (e.g., Rh+, Pd2+, Cu+, Zn2+).2
Thus, to dissolve the corresponding salts, a polar solvent is
required. (ii) To achieve high reaction rates, the metal center
should be only weakly coordinated by the solvent. (iii) The
solvent for the catalyst phase has to be immiscible with an
appropriate apolar organic solvent over a wide temperature
range. (iv) Water can not be used in the addition of RNH2 to CC
triple bonds, as it reacts with the imines formed. Therefore, the
ionic liquid 1-ethyl-3-methylimidazolium trifluoromethane-
sulfonate was chosen as the polar phase.7 This salt is liquid over
the required temperature range (rt to > 350 °C) and is
chemically relatively inert. The metal salt Zn(CF3SO3)2 was
chosen as the catalyst. Zinc(II) seemed particularly stable
against deactivation as it cannot be reduced to the metal under
the reaction conditions. Toluene and heptane were chosen as the
apolar phase and solvent for the starting material and product. In
the presence of amines, Zn(CF3SO3)2 is soluble in small
amounts in toluene, which allows a direct comparison with the
corresponding homogeneous catalysis. In contrast, the less
(3)
The cyclisation of 6-aminohex-1-yne first generated the
enamine 2-methylenepiperidine, which isomerised in situ to the
corresponding imine 2-methyl-1,2-dehydropiperidine (eqn. 1).
In the two-phase system, a quantitative conversion (499%) of
6-aminohex-1-yne was achieved within 150 min.† Under equal
reaction conditions, the rate of reaction in the two-phase system
was higher than in the corresponding homogeneous catalysis
using Zn(CF3SO3)2 as the catalyst (Fig. 1). Possibly, a polar
transition state is stabilised in the presence of 1-ethyl-
3-methylimidazolium trifluoromethanesulfonate leading to a
higher rate of reaction.8 In the presence of the ionic liquid, the
concentration of zinc ions in the toluene phase (range 0.2–1.2 3
1023 g dm23) was three orders of magnitude lower than during
the homogeneous catalysis (1.3 g dm23). Thus, the reaction in
the two-phase system occurs either in the polar phase or at the
phase boundary. Both two-phase and homogeneous reaction
followed approximately first order kinetics. Compared to the
corresponding heterogeneous (solid–liquid) catalysis using Zn-
beta as catalyst, the rate of reaction in the liquid–liquid two-
phase system was slightly lower. For this heterogeneous system
† Electronic supplementary information (ESI) available: experimental
Fig. 1 Time-concentration diagram for the conversion of 6-aminohex-1-yne
details. See http://www.rsc.org/suppdata/cc/b1/b111630d/
in a heterogeneous, a two-phase and a homogeneous catalyst system.
906
CHEM. COMMUN., 2002, 906–907
This journal is © The Royal Society of Chemistry 2002

it had been shown that the high catalytic activity is due to the
presence of protons in the solid material, which function as co-
catalyst.5 In contrast, the two-phase catalysis was performed
under neutral conditions. This extends the scope of the reaction
to those substrates that have additional acid sensitive functional
groups.
The reaction between phenylacetylene and aniline gives
phenyl-(1-phenylethylidene)-amine (eqn. 2). This reaction was
much slower than the cyclisation of 6-aminohex-1-yne. After
150 min, about 10% conversion was achieved. Whereas the
combined concentrations of phenylacetylene and product in the
toluene phase added up to the initial concentration of phenyl-
acetylene, about half of the initially added aniline was not
found. The missing aniline was probably present in the ionic
liquid, and was, therefore, not observed by GC analysis. The
unfavourable phase equilibrium for aniline might be the reason
for the low rate of reaction. The cyclisation of 3-aminopropyl
vinyl ether to tetrahydro-2-methyl-1,3-oxazine was consider-
ably faster (eqn. 3). Quantitative conversion was achieved
within 10 min (rate 4 1.6 3 1022 mol (molZn s)21), which was
2+
much faster than in the corresponding homogeneous catalysis
2+
Fig. 2 Model for the two-phase catalysis of hydroamination reactions.
with Zn(CF3SO3)2 (rate 7.2 3 104 mol (molZn s)21).2
enables a nucleophilic attack of the amine on the p-system and
yields an ammonio alkenyl complex. The latter is energetically
unfavourable because of the charge separation. Stabilising this
complex, respectively a preceding or succeeding polar transi-
tion state, in a highly polar solvent increases the overall rate of
reaction. A formal 1,3-hydrogen shift gives the product
enamine, which desorbs and isomerises to the corresponding
imine. Either the enamine or the imine diffuses back into the
bulk heptane phase.
In summary, it was shown that hydroamination reactions can
be efficiently catalysed in a liquid–liquid two-phase system. For
the first time, an ionic liquid (1-ethyl-3-methylimidazolium
trifluoromethanesulfonate) was employed successfully as a
polar solvent in this type of reaction. The catalyst Zn(CF3SO3)2
was fixed efficiently in the ionic liquid, whereas the product
phase was readily separated. It is particularly noteworthy that
the presence of a highly polar solvent led to a higher intrinsic
rate of reaction compared to the corresponding homogeneous
catalysis. We speculate that this is induced by the better
stabilisation of the polar transition state at the ionic liquid
interface. The CSTR used in the experiments proved well suited
for determining the reaction rate. For an efficient two-phase
catalysis of hydroamination, such as the cyclisation of 6-amino-
hex-1-yne, the reactor needs to be designed such that the area of
the interface is maximised.
For a more detailed exploration of the two-phase system, a
custom built autoclave was filled with the catalyst phase (34.5
cm3) and pure heptane (35.5 cm3).† Both phases were stirred
separately in such a way that the phase boundary (area 3.5 cm2)
remained steady. The reactor was equilibrated with a steady
flow of heptane and operated at 40 bar. The reaction was then
started by switching to a solution of the substrate in heptane. For
a non reactive internal standard (hexadecane) and a flow of 10
cm3 min21, an exponential increase in concentration was
observed after a dead time of 0.8 min. The residence time
distribution (RTD) of the internal standard shows that the
hydrodynamic flow pattern of the reactor was close to an ideal
continuously operated stirred tank reactor (CSTR). At 10 cm3
min21 the average residence time was 4.4 min and steady state
was reached 13 min after the dead time.
When the experiment was performed with 6-aminohex-
1-yne, the sum of the concentrations of starting material and
product reproduced that of the internal standard well. This
indicates that only little substrate or product diffused into the
ionic liquid. At 110 °C and 10 cm3 min21, 4% of 6-aminohex-
1-yne was converted to 2-methyl-1,2-dehydropiperidine in the
steady state, which corresponds to a formal macrokinetic
reaction rate of 3.3 3 1023 mol m23 s21. This corresponds to a
rate of 0.11 mol m23 s21 marea22 when normalised to the area
of the interface. No decrease in the rate of reaction was observed
over longer periods (6 h) of operation. If run in the batch mode,
a quantitative conversion (499%) was achieved after 6.5
hours.
The support of Deutsche Forschungsgemeinschaft and Dr-
Ing Leonhard-Lorenz-Stiftung is acknowledged. Dr L. Callanan
and Dr E. Bratz are thanked for proof-reading the manuscript.
The conversion increased exponentially with temperature
and linearly with residence time.† From the temperature
dependence, an apparent activation energy of 28 8 kJ mol21
was calculated. The linear variation of the conversion with
residence time and the equal apparent energy of activation at all
residence times strongly implies the absence of external
diffusion limitations across the phase boundary. Upon reduction
of the reaction area from 3.5 cm2 to 1.8 cm2, the conversion
dropped by the same factor (flow 2.5–10 cm3 min21). The linear
correlation between the geometric area of the phase boundary
and the reaction rate indicates that the catalytic reaction takes
place directly at the interface of the two phases. The zinc ion
concentration in the product phase was close to the detection
limit of AAS (50.07 mg dm23). This confirms that most of the
reaction occurs at the phase boundary. The increase in reaction
area is, therefore, the most effective way to increase the
conversion with equal residence time.
Notes and references
1 T. E. Müller and M. Beller, Chem. Rev., 1998, 98, 675.
2 T. E. Müller, M. Berger, M. Grosche, E. Herdtweck and M. F. P.
Schmidtchen, Organometallics, 2001, 20, 4384; R. Q. Su and T. E.
Müller, Tetrahedron, 2001, 57, 6027; T. E. Müller and A.-K. Pleier, J.
Chem. Soc., Dalton Trans., 1998, 4, 583.
3 See also, e.g., M. Kawatsura and M. J. F. Hartwig, Organometallics,
2001, 20, 1960; C. G. Hartung, A. Tillack, H. Trauthwein and M. Beller,
J. Org. Chem., 2001, 66, 6339.
4 M. K. Richmond, S. L. Scott and M. H. Alper, J. Am. Chem. Soc., 2001,
123, 10521.
5 J. Penzien, T. E. Müller and M. J. A. Lercher, Microporous Mesoporous
Mater., 2001, 48, 285; R. S. Neale, L. Elek and R. E. Malz, J. Catal.,
1972, 27, 432.
6 S. Cacchi, V. Carnicelli and M. F. Marinelli, J. Organomet. Chem., 1994,
475, 289.
7 For reviews on ionic liquids see: R. Sheldon, Chem. Commun., 2001,
2399; Charles M. Gordon, Appl. Cat. A, 2001, 222, 101; J. F. Brennecke
and E. J. Maginn, AIChE Journal, 2001, 47(11), 2384.
8 See Y. Marcus, The Properties of Solvents, ed. P. G. T. Fogg, John Wiley
& Sons, Chichester, 1999, vol. 4, p. 187.
A model of the elementary steps of the reaction is shown in
Fig. 2 based on recent mechanistic studies.2,9 Once the
6-aminohex-1-yne has diffused from the bulk heptane phase
into the layer directly adjacent to the phase boundary, it
coordinates to the zinc cations via the CC multiple bond. This
9 H. M. Senn, P. E. Blöchl and M. A. Togni, J. Am. Chem. Soc., 2000, 122,
4098.
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