Trifluoroacetic Acid Hydroxylamine System as Organocatalyst Reagent in a One-Pot Salt Free Process for the Synthesis of Caprolactam and Amides of Industrial Interest

Article abstract of DOI:10.1007/s10562-021-03590-z

In this work we studied the reactivity of the Trifluoroacetic acid hydroxylamine system in the one step salt free synthesis of amides from ketones. A particular regards was paid to the caprolactam synthesis because of its industrial relevance. Synthesis, reactivity and characterization of the hydroxylamine trifluoroacetate is given. Fast oximation reaction of several ketones was gained at room temperature (1?h of reaction quantitative conversion for several ketones). In the same reactor, by raising the temperature at 383?K, the Beckmann rearrangement of the so obtained oximes is easily accomplished in the presence of three equivalent of TFA. The possibility of obtaining the trifluoroacetate of the hydroxylamine with a modified nitric acid hydrogenation reactions was verified, too. Reuse of solvent and trifluoroacetic acid is easily achieved by distillation. Graphical abstract: Salt free one-pot caprolactam and amides process catalyzed by CF₃COOH, in the presence of NH₂OH TFA as the oximation agent.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-021-03590-z

Catalysis Letters
https://doi.org/10.1007/s10562-021-03590-z
Trifuoroacetic Acid Hydroxylamine System as Organocatalyst Reagent
in a One‑Pot Salt Free Process for the Synthesis of Caprolactam
and Amides of Industrial Interest
F. Manente1 · L. Pietrobon1 · L. Ronchin1 · A. Vavasori1
Received: 9 December 2020 / Accepted: 1 March 2021
© The Author(s) 2021
Abstract
In this work we studied the reactivity of the Trifuoroacetic acid hydroxylamine system in the one step salt free synthesis of
amides from ketones. A particular regards was paid to the caprolactam synthesis because of its industrial relevance. Synthe-
sis, reactivity and characterization of the hydroxylamine trifuoroacetate is given. Fast oximation reaction of several ketones
was gained at room temperature (1 h of reaction quantitative conversion for several ketones). In the same reactor, by raising
the temperature at 383 K, the Beckmann rearrangement of the so obtained oximes is easily accomplished in the presence of
three equivalent of TFA. The possibility of obtaining the trifuoroacetate of the hydroxylamine with a modifed nitric acid
hydrogenation reactions was verifed, too. Reuse of solvent and trifuoroacetic acid is easily achieved by distillation.
Graphical abstract
Salt free one-pot caprolactam and amides process catalyzed by CF3COOH, in the presence of NH2OH TFA as the oxima-
tion agent.
NOH
O
O
T 298K
CH3CN
T 383K
CH3CN
N
.
CF3COOH
+
CF3COOH
+
CF3COOH
NH2OH
+
CF3COOH
CF3COOH
Distillation
CF3COOH CH3CN
Keywords Oximation · Beckmann rearrangement · Hydroxylamine trifuoroacetate · Trifuoroacetic acid
1 Introduction
are real waste, whose disposal decreases the sustainability of
the whole process [2]. Recently, salt free processes are running
in the Far East by employing a step of cyclohexanone amoxi-
mation and a second step of Beckmann rearrangement in gas
phase [1]. The Eni amoximation step and the Sumitomo gas
phase rearrangement are the core of this salt free processes.
More recently, Sinopec has claimed similar route employing
both an amoximation step and a gas phase rearrangement [3].
In both cases, however, a complete transformation of the tra-
ditional plants, based on liquid phase reactions, needs for run-
ning this type of process. In fact, the revamping of existing
plant in Europe and USA could be a more economically and
environmentally sustainable way, since the demand caprolac-
tam in the western regions does not growth as in the Far East
[1, 4–6]. Starting from such an idea, of having small plant
Caprolactam is a chemical whose importance raises continu-
ously from the beginning of its industrial production being
the monomer of the important polyamide nylon 6. Despite of
the large number of studies a defnitive waste free a process
is not available until now [1]. Problems of coproduction of
side products of low economic value afects current industrial
processes, or in additions, for certain cases these coproduction
* L. Ronchin
ronchin@unive.it
1
Department of Molecular Sciences and Nanosystems,
University Ca’ Foscari of Venice, via Torino155 30170,
Mestre, Venezia, Italy
Vol.:(0123456789)
1 3

F. Manente et al.
modifcation for caprolactam process, a need of integrated one
pot liquid phase reactions are of interest from both economics
and environmental point of view. For this reason the research
in this feld is in continuous development and only in the last
two years has appeared several papers and, in addition, two
comprehensive review on the argument [7, 8]. The oximation
step occurs generally in high selectivity but in the presence
of a stoichiometric amount of a base, which leads to the for-
mation of the salt deriving from neutralization of the acid of
the hydroxylammonium salt, is the main concern of this step.
Actually, this byproducts is one of the main issue of the whole
process [1, 2]. Recently, literature have reported new method-
ologies giving good yields in ketones oximation carried out in
ionic liquids, so that avoiding the neutralization [9]. Besides
organocatalysts improves such a step by increasing the yield
in the oximes formation, particularly useful for ketones with
low reactivity, especially for those with steric hindrance at the
carbonyl. [10].
agent (hydrochloride is the preferred), since a purifcation from
hydrochloric acid or other mineral acid present in the reaction
environment must be considered in an industrial application
of the reaction.
Starting from these considerations, it is clear that the
main concern of the whole one-pot process is strictly
related to the hydroxylamine in the reaction environment,
in fact, hydroxylammonium salt are sparingly soluble. For
this reason the oximation process are slow, thus needs quite
high temperature in order to achieve partial dissolution, for
increasing formation of free oxime, and fnally to speed up
reaction rate [25]. Furthermore, it is necessary to take into
account that the use of liquid hydroxylamine is not indus-
trially desirable due to the intrinsic instability of the com-
pound, which may cause devastating explosion in plants as
already occurred in the CSI plant of Allentown Pennsylvania
on February 1999 [26]. Nowadays, the industrial produc-
tion of hydroxylamine arises mainly from three processes:
Rashig, BASF-Inventa and HPO-DSM [27]. In any case,
these processes are all based on the reduction of nitrites,
NOx and nitric acid in solution of mineral acids, the latter
stabilize the hydroxylamine produced to the correspond-
ing hydroxyl ammonium salt [27]. The direct formation of
hydroxylamine from ammonia oxidation is practicable by
the direct amoximation of ketones by following the above-
mentioned Eni process [1]. In this case, ketone consumes
immediately the hydroxylamine produced by the oxidation
reaction thus directly forming the oxime. Furthermore, the
reaction occurs in an aqueous solution of isopropyl alcohol,
which reduces the risk of decomposition and explosion of
the hydroxylamine eventually in solution [1]. The use of
such a solvent, however, in the amoximation process does
not allow a further Beckmann rearrangement, particularly,
by using the trifuoroacetic acid (as organocatalyst) in a one-
pot process [15–18]. Then under such conditions, the recov-
ery of the oximes from the solvent became necessary for the
further step of Beckmann rearrangement. This further step
diminishes the sustainability of the rearrangement catalyzed
by trifuoroacetic acid in combination with an amoximation
stage. Starting from these evidences, it appears that oxima-
tion of ketones is the weak stage of an all-liquid phase syn-
thesis of amides in one-pot. In fact, either, direct oximation
of ketones with a hydroxylammonium salt of a mineral acid,
or their amoximation, do not let a direct Beckmann rear-
rangement step, but separation and purifcation step needs.
In this paper, we want to show some results on the syn-
thesis and use of the ionic liquid hydroxylammonium tri-
fuoroacetate as oximation agent for ketones in very mild
Recently, the chemistry of trifuoroacetic acid as organo-
catalyst has been suggested for the synthesis of the caprolac-
tam, of other amides as well as to several other reactions of
industrial interest [7–16]. For instance, some authors proposed
the direct oximation and rearrangement of ketones and in par-
ticular, of the cyclohexanone, to the corresponding amides
[15–20]. The second important process in term of amide pro-
duced is the Hoechst-Celanese process for the synthesis of
the N-acetyl-4-aminophenol (acetaminophen). The produc-
tion of such an important drug is in continuous growth [21].
The existing processes are based on several type of reactions,
one of the most employed is actually the Hoechst-Celanese
process where 4-hydroxy acetophenone reacts with hydroxy-
lamine giving the corresponding oxime, which rearranges to
the N-acetyl-4-aminophenol in the presence of thionyl chloride
[22]. In this case, two steps are necessary to carry out the syn-
thesis: an oximation stage and the Beckmann rearrangement
[22]. A simplifcation of the process can be attained by carry-
ing out these two latter stages in one-pot [23]. During the last
decade our research group, Luo and coworkers have published
independently some papers where oximation and Beckmann
rearrangement occur in one pot in high yield [15–19, 23]. The
kernel of the process is using a mixture of trifuoroacetic acid
and acetonitrile, which allows high yield in the amides [15–18,
23]. More recently, we pointed out that the two reactions,
when the temperature is increased over 383 K, proceeds also
in absence of trifuoroacetic acid (though in lower yield) and
the reaction is self-catalyzed by the hydroxylammonium salt
[24]. It appears (see Scheme 1) that the major weakness of this
reaction is the use of hydroxylammonium salt as oximation
Scheme 1 Oximation of a
ketone and Beckmann rear-
rangement in TFA
1 3

Trifuoroacetic Acid Hydroxylamine System as Organocatalyst Reagent in a One‑Pot Salt Free…
condition. We want to show also the complete compatibility
with a further step of Beckmann rearrangement catalyzed
by trifuoroacetic acid. Finally, a very preliminary result on
a modifed HPO process for the synthesis of such an ionic
liquid is also given. The fnal aim of this preliminary work is
that of proposing a practical liquid phase salts free synthesis
of caprolactam and amides in general.
spectrum (ESI–MS) where carried in a Waters Micromass
ZQ by direct injection of a 1 ppm TAH solution in ace-
tonitrile. Hydroxylamine trifuoroacetate were synthesized
by an exchange procedure in aqueous solution. A typical
preparation was carried out as follow: hydroxylamine sul-
fate was dissolved in water (c.a. 10 wt. %). A solution of
Ba(OH)2 5% is neutralized with TFA plus an addition of a
small excess of TFA until pH=3, this is useful to complete
the exchange of the sulfate ions in the second step. The
slowly addition of the hydroxylammonium sulfate solution
allow the precipitation of BaSO4 and in solution remains
NH2OH·CF3COOH (TAH). The separation of the surnant-
ant solution by centrifugation it allows recovering TAH
after the evaporation of the water in a rotary-evaporator
at 343 K under vacuum (mechanical pump 1000 Pa). The
resulting viscous oil is then left at 343 K under higher
vacuum (0.2 Pa) for 2 h. TAH is a viscous colorless liquid
and it was characterized by TGA–DSC, NMR, and electric
conductivity, the latter measurements states that the com-
pound has an ionic conductivity (all the measurements are
in supplementary materials).
2 Experimental
All solvents and reagents were employed as received
without further purification. Trifluoroacetic acid 98%
(TFA) Carlo Erba, cyclohexanone 99% (CON), acetophe-
none 99%, 4-Hydroxyacetophenone ≥ 98%, 2-hydroxy-
acetophenone ≥ 95%, 2-methyl-acetophenone ≥ 98%,
4-Br-acetophenone 98%, 4-NO2-acetophenone 98%,
2,4,6-trimethyl-acetophenone ≥ 98%, cyclohexanone
oxime (COX), acetanilide, N-acetyl-4-aminophenol, cap-
rolactam (CPL), trifuoroacetic acid (TFA) 99%, hydroxy-
lamine hydrochloride (Cl–H) 99%, hydroxylamine Sulfate
99% (SO4-2H), hydroxylamine phosphate 99% (PO4-3H),
diethyl ether (Et2O), acetonitrile, ethanol (EtOH), dime-
thyl carbonate (DMC), dichloromethane, tetrahydrofuran
(THF), and dioxane were all Merck solvent grade prod-
ucts. Deuterated chloroform and deuterated acetonitrile
were Merck products. Analyses of the reactions were car-
ried out with gas chromatograph (GC) an Agilent 6890
equipped with FID or on chromatograph coupled mass
spectrometer (GC–MS) Agilent 7890A equipped with
a MS detector (Agilent 5975C) both instruments with
a HP 5 column (I.D. 320 μm, 30 m long, same column
in both the). Helium was employed as carrier under the
following conditions: injector 523 K, detector 543 K,
fow 1 mL min−1, oven 333 K for 3 min to 523 K at 15 K
minute−1 and 523 K for 15 min. Calibration with stand-
ard solutions of the pure products allows the calculation
of yield and selectivity. In order to verify the presence
of thermo-labile substances some samples were analysed
by HPLC (Perkin Elmer 250 pump, LC 235 diode array
detector and a C 18, 5 μm, 4 mm i.d. 25 cm long column,
using CH3CN-H2O as mobile phase, in isocratic CH3CN
All the reactions were carried out in a well stirred glass
reactor thermostated at temperatures comprised between
298 K and 318 K, containing weighed samples of the
solvent and reagents. In a typical experiment was loaded
10 mmol of the selected ketone, 30 mmol of NH2OH·X
(where X=CF3COOH, HCl, H2SO4, H3PO4), 10 mL of sol-
vent (CH3CH2OH, CH3CN, DMC, CH2Cl2), and, if required,
30 mmol of TFA, reaching the fnal volume of reaction of
about 12 mL.
The Beckmann rearrangement step were carried out in the
same reactor used for the oximation plugged into a 20 mL
autoclave in order to accomplish Beckmann rearrangement
at temperature of 383 K, which is higher than that of the
boiling point of the solvent (acetonitrile 355 K).
Analysis of reaction products were carried by GC,
GC–MS, HPLC and NMR. In the selectivity calculations
TFA peak has not been considered, while the traces amount
of the ester COX-TFA is added to the COX peack. The 1H
and 13C NMR spectra were recorded at 298 K. NMR spec-
tra were obtained from the mixture of reaction after purif-
cation by vacuum distillation. Typically, the product is an
oil, which was washed with dichloromethane, dried with
anhydrous sodium sulfate, and the solvent eliminated in a
rotary evaporator. Spectra and analytical details in are sup-
plementary materials.
1
70%, at 1 mL min−1). H and 13C NMR measurements
were carried out in a Brucker Avance 400 II at 400 MHz
and 100 MHz, respectively, in CDCl3, CD3CN or D2O as
the solvent. Impedance measurements were carried out
on a Solartron SI1260 gain phase analyzer, employing a
Pt conductivity cell with a 0.998 cm−1 constant in water
or acetonitrile as a solvent at a Hydroxylamine trifuoro-
acetate concentration of 0.05 mol L−1. DSC-TGA meas-
urements were carried out on a Linseis TGA1000 in an
aluminum crucible under an air fow of 100 mL min−1 and
a temperature ramp of 10 K min−1. Electron spray mass
Preliminary experiments of nitric acid hydrogenation in
aqueous TFA as a solvent (12 mL of HNO3 0.25 mol L−1 in
aqueous TFA at 10%) were carried out in an agitated glass
reactor at 308 K for 8 h, at atmospheric pressure under
hydrogen fow of 30 mL min−1. Nitric acid conversion and
hydroxyl amine formation are measured by spectrophoto-
metric analysis [28].
1 3

F. Manente et al.
the presence of TFA is mandatory to have in the second
step, that is the Beckmann rearrangement of the oxime,
high conversion and selectivity in CPL, for this reason
we tested the reactivity of the various oximation agent in
the presence of TFA in the optimal concentration for the
Beckmann rearrangement [15–18]. The presence of TFA
causes the reduction of the selectivity in COX especially
at longer reaction time, because of the increases of the
condensation products of CON catalyzed by TFA. In fact,
CON, which is stable in acetonitrile solution at 298 K, in
the presence of TFA, it shows condensation products (see
Table 1). The reason of such a reactivity of TAH can be
ascribed to its complete solubility in acetonitrile or in the
mixture acetonitrile TFA. In addition, just the selectivity
is unafected by the presence of the TFA, while with other
oximes decreases.
3 Results and Discussions
3.1 Infuence of the Oximation Agent
in the CON‑ > COX‑ > CPL Process
Oximation reaction is a nucleophilic one and the actual
reagent is the NH2OH. As a matter of fact, in the usual
organic synthesis the use of a strong base, such KOH
or NaOH, it allows the neutralization of the acid of the
hydroxylammonium salt, and the formation of free
NH2OH with the consequent formation of a stoichiometric
amount of the sodium or potassium salt of the acid. The
high reactivity of the free NH2OH, though hydroxylam-
monium salt are sparingly soluble in non-aqueous organic
solvent, allows the formation of the oxime. However, it
arises at quite high temperature or long time of reaction.
Table 1 shows the reactivity of diferent oximation agent
on CON conversion to COX in acetonitrile as the solvent.
It appears that practically only TAH achieves quantita-
tive conversion after 1 h of reaction, either in the pres-
ence of TFA or in its absence (at longer time of reactions
a very small increase of the condensation byproducts is
observed about 2%). In the presence of other hydroxyl
ammonium salts, reactions have shown lower conversion
and selectivity. Only the reaction with Cl–H has reached
78% of conversion after 20 h of reaction. It is noteworthy
Table 2 reports the reactivity in the second step of the
process that is the Beckmann rearrangement catalyzed by
TFA or, eventually, by the acid deriving from the hydrox-
ylammonium salt. It appears that only in the presence of
an excess of TFA conversion to CPL occurs in practical
interesting yield. As a matter fact, in the presence of TFA/
COX=3 it achieves practically quantitative conversion and
selectivity of 97–98% in CPL after one hour of reaction only
in the presence of TAH. In other cases, reactions appear
incomplete (even though quite good results it is achieved
after 20 h of reaction with Cl–H) and several condensation
Table 1 Reactivity of diferent
Oximation agent
Time of reac- TFA (TFA/
Conversion COX sel. (%)
(%)
Other sel.1 (%)
oximation agents toward CON
tion (h)
CON)
/
1
1
1
1
0
0
0
0
0
0
0
0
0
3
3
3
3
3
3
3
3
3
0
0
0
1
11
13
15
3
TAH
99
32
24
18
99
78
79
65
3
99
30
24
18
99
78
77
65
99
89
87
85
97
91
87
84
0
98
88
82
79
96
91
85
83
Cl–H
SO4-2H
PO4-3H
TAH
Cl–H
SO4-2H
PO4-3H
/
1
20
20
20
20
1
1
1
1
1
20
20
20
20
9
13
16
100
2
12
12
14
4
TAH
Cl–H
SO4-2H
PO4-3H
TAH
Cl–H
SO4-2H
PO4-3H
9
13
15
Run conditions: T 298 K, reaction volume 12 mL, CON 0.8 mol L−1, hydroxyl amine/CON=3, CH3CN as
the solvent
1Other are mainly cyclohexanone condensation products
1 3

Trifuoroacetic Acid Hydroxylamine System as Organocatalyst Reagent in a One‑Pot Salt Free…
Table 2 Reactivity of the
second step in Beckmann
rearrangement in the presence
of diferent oximation agent
Oximation agent
Time of reac-
tion (h)
TFA (TFA/
COX)
Conversion CPL sel. (%)
(%)
Other sel.1 (%)
/
20
20
20
20
20
1
1
1
1
1
20
20
20
20
0
0
0
0
0
3
3
3
3
3
3
3
3
3
3
5
0
2
100
98
98
98
98
100
3
12
66
49
2
TAH
Cl–H
SO4-2H
PO4-3H
/
6
4
2
2
3
8
2
0
TAH
99
30
24
18
99
98
77
65
97
88
34
51
98
95
50
48
Cl–H
SO4-2H
PO4-3H
TAH
Cl–H
SO4-2H
PO4-3H
5
50
52
Run conditions: T 383 K, reaction volume 12 mL, CH3CN as the solvent, COX 0.8 mol L−1
1Other are mainly cyclohexanone condensation products
products of CON are in the reaction mixture after 20 h
of reaction. The formation of such condensation prod-
ucts can be explained by the presence of unreacted CON,
which causes these unwanted condensation reactions at the
increasing of the temperature to 383 K, necessary to achieve
a quite fast Beckmann rearrangement of the COX [15–18].
This agrees with the results of the control reactions carried
out without oximes, in which CON condensations products
are the only molecules detected. Besides, these side-reac-
tions favors COX hydrolysis further, because of formation
of water and alcohols, thus determining an extra reduction
of the selectivity in CPL. The formation of condensation
products are parallel reactions, since CON in the presence
of TFA after 1 h of reaction at 383 K gives, a conversion
of 8% to such condensation compounds. In addition, in the
presence of hydroxylammonium salts and no TFA, COX
forms mainly CON and its condensation products, while, if
TAH is in reaction medium, it minimizes hydrolysis to CON
together with its condensation products.
3.2 Infuence of Solvents and of the Operative
Variables on Oximation of CON with TAH
Followed by Beckmann Rearrangement to CPL
Table 3 shows the infuence of various solvents on the reac-
tivity of the TAH in the CON oximation and Beckmann rear-
rangement. CH3CN as a solvent gives the best results, since
in such a solvent both the oximation and the rearrangement
steps occur easily. In the other tested solvents, the oxima-
tion takes place in high conversion and selectivity in COX,
Table 3 Reactivity of TAH
Oximation
Beckmann rearrangement
toward CON oximation and
Beckmann rearrangement in the
presence of various solvent
Solvent
CON conver- COX selectiv- Other selectiv- COX conver- CPL selectiv- Other1
sion (%)
ity (%)
ity (%)
sion (%)
ity (%)
selectivity
(%)
CH3CN
Toluene
Dioxane
THF
EtOH
DMC
99
92
99
99
99
99
99
99
98
97
98
99
95
94
1
1
3
2
1
5
6
99
98
8
7
5
2
2
97
96
89
90
45
2
3
3
11
10
55
98
95
Et2O
5
Run conditions oximation step: T 298 K reaction volume 12 mL, CON 0.8 mol L−1, hydroxylamine/
CON=3, time of reaction 1 h. Beckmann rearrangement step T 383 K, time of reaction 1 h
1Cyclohexanone and cyclohexanone condensation products
1 3

F. Manente et al.
Table 4 Reactivity of TAH in the oximation of several ketones
but the second step occurs in much lower conversion and
selectivity. For instance, toluene, dioxane and THF shows a
quite high selectivity in CPL but conversion of COX is very
low, while in EtOH, DMC and Et2O CPL is formed only in
few percent of yield. Toluene as the reaction solvent gives
lower oximation yield (conversion 94% selectivity 98%), but
it appears to be a good solvent for the second step where
96% selectivity to CPL is achieved. Actually, CH3CN appear
to be however, the best solvent for such a process, this is in
agreement with previous results in which specifcally this
solvent were recognized as the best solvent for the Beck-
mann rearrangement catalyzed by TFA [15–18].
Ketone
Time of
reaction
(h)
TFA
Con-
version
(%)
Oxime sel. (%) Other
(TFA/
CON)
sel.
(%)
CON
ACP
1
1
0
0
0
0
0
0
0
0
3
3
3
3
3
3
3
3
99
99
0
99
99
0
1
1
0
1
3
5
5
4
2
3
0
4
4
6
5
4
2,4,6-TMA 201
4-OHACP
4-MeACP
2-MeACP
2-MeACP 20
4-NO2ACP
CON
1
1
1
99
98
77
77
96
99
99
0
99
98
75
77
94
99
97
952
952
96
98
97
0
96
96
942
952
96
1
1
1
3.3 Reactivity of TAH Towards Diferent Ketones
ACP
2,4,6-TMA 201
TAH shows high reactivity toward all ketones in the oxima-
tion reaction, in fact in all cases high conversion and selec-
tivity is achieved in 1 h at 298 K. As expected 2,4,6 trimethyl
acetophenone (2,4,6-TMA) does not react since the nucleo-
phile does not approach to the carbonyl because of the steric
hindrance of the methyl group in 2- and 6- position of the
phenyl. This efect on the reactivity of the TAH is the same
for the reactivity of the free hydroxylamine in aqueous sol-
vent, in which the same steric efect with ortho- substituents
were observed [29]. Such a behavior of the hydroxylamine
as nucleophile suggests that the role of the trifuoroacetate
is not determining the reactivity of the hydroxylamine itself,
but, likely, it acts on the solubility of the ionic specie. In fact,
a single phase is achieved with TAH while with the other
hydroxylammonium salts a solid phase is always present.
From practical point of view it is noteworthy the high
conversion and selectivity for the 4-OH-acetophenone
(4-OHACP) would suggest a new route for the synthesis
of acetaminophen (N’acetyl-4-aminophenol) in a waste free
process and in one pot reaction [23]. In fact, the use of TAH
will allow the synthesis of such a compound without salts
coproduction and with a complete reuse of solvent and TFA.
In this table for the sake of clearness we report the reac-
tivity of only the 2-MeACP (other isomers are in the sup-
plementary materials Table S1) since both E and Z oximes
are obtained and the reason of this diference with respect to
the other ketones is beyond the aim of the present work and
it needs further investigations (Table 4).
4-OHACP
4-MeACP
2-MeACP
2-MeACP 20
4-NO2ACP
1
1
1
1
Run conditions: T 298 K, reaction volume 12 mL, ketone 0.8 mol
L−1, TAH / ketone=3, CH3CN solvent
1Preparation of 2,4,6-trimethyl acetophenone oxime requires actu-
ally very long reaction time, but under this conditions no reaction has
been observed after 30 days[29]
2Selectivity is the sum of the selectivity of the two isomers
0.25
0.20
HNO3
NaNO3
NH2OH/HNO3
NH2OH/NaNO3
0.15
0.10
0.05
0.00
0
2
4
6
8
Time (h)
Fig. 1 Reaction profle of Nitric acid hydrogenation. Run conditions:
Catalyst Pd/C 10% 50 mg, solvent aqueous TFA 10%, pressure 1 bar,
hydrogen fow 20 mL min−1, substrate concentration 0.25 mol L−1
reaction volume 20 mL
3.4 Preliminary Results on HNO3 Hydrogenation
in TFA for the Direct Synthesis of TAH
The use of TAH, as oximation agent for cyclohexanone as
intermediate in the caprolactam production, is interesting, if
it is available an easy way to obtain such a reagent without
using complex procedure or multistep process. The HNO3
hydrogenation DSM-HPO process gives directly hydroxy-
lamine phosphate salt, now we try to verify the feasibility of
a modifcation of such a process in order to obtain directly
the TAH by hydrogenation of the nitric acid [27]. In Fig. 1
a reaction profle of nitric acid hydrogenation is reported.
It is noteworthy that there is a negligible diference in the
reactivity of HNO3 or its sodium salt, suggesting sodium
1 3

Trifuoroacetic Acid Hydroxylamine System as Organocatalyst Reagent in a One‑Pot Salt Free…
cation does not infuence the overall reactivity. Conversion
does not reach completeness after 8 h of reaction however
at higher temperature and pressure a complete conversion
is reached but at lower overall yield of TAH. As a matter of
fact, complete hydrogenation of hydroxylamine to ammo-
nium hydroxide occurs at higher temperature and pressure.
The process appears a complex pattern of parallel and con-
secutive reaction whose optimization is beyond the scope of
this preliminary work.
References
1. Rivetti F, Buzzoni R, in Liquid Phase Oxidation via Heterogene-
ous Catalysis: Organic Synthesis and Industrial Applications, Eds.
Clerici M. G, Kholdeeva O. A, (Wiley New York 2013) 462–496.
2. Fisher WB, Crescentini L. Staf U, in Kirk Othmer Encyclopedya
of Chemical Technology, Vol. 4 (Wiley New York 2015) 1–11 on
line eds.
3. Bin S, Wei W, Enze M, Ye X (2007) China Pet Process Pe 7:25
4. Fisher G (2003) Fibers Text East Eur 11:1114
5. Van der Linde S, Fisher G (2004) Fibers Text East Eur 12:17
6. https://chemicalmarketresearchnews.wordpress.com/2019/06/
28/market-leader-caprolactam-market-key-players-global-forec
ast-to-2027/.
4 Conclusions
7. Kumar R, Prangya SS, Das P, Bhabavanbhai GGK, Al Fatesh A,
Chowdhury B (2019) Catal. Rev. 61:516
The reactivity of TAH and that of TFA for an integrated pro-
cess from ketones to amides has been verifed. It appears that
TAH as oximation agent results generally more active than
the mineral acid oxime salts. In fact almost all the ketones
undergo oximation in 1 h at room temperature. The reason of
such a behavior it has been ascribed mainly to the complete
solubility of the compound in the various solvents employed
for the reactions rather than to a specifc reactivity of the
ionic liquid. The more useful behavior of the compound in
this consecutive reactions is however, the formation of TFA
after the oximation step, which is necessary for the further
step of Beckmann rearrangement. Furthermore, TFA does
not negatively afect the oximation step and it can be added
in quite large excess directly in the frst stage of the process.
The Beckmann rearrangement however occurs easily in the
same reaction environment but temperature must be raised
at 383 K to achieve complete conversion in 1 h of reac-
tion. Finally the possibility of the synthesis of the TAH via
a modifed HPO process in which the ionic liquid can be
obtained directly from HNO3 hydrogenation in the presence
of TFA has been preliminarily demonstrated. Reuse of sol-
vent and trifuoroacetic acid is easily achieved by distillation.
8. Kaur K, Srivastava S (2020) New J Chem 44:18530
9. Karthikeyan P, Aswar SA, Muskawar PN, Sythana SK, Bhagat
PR, Kumar SS, Satvat PS (2016) Arab J Chem 9:S1036
10. Crisalli P, Kool ET (2013) J org chem 78:1184
11. Marziano NC, Ronchin L, Tortato C, Vavasori A, Bortoluzzi M
(2008) J Mol Catal A Chem 290:79
12. Ronchin L, Vavasori A, Bortoluzzi M (2008) Catal Commun
10:251
13. Ronchin L, Vavasori A, Bortoluzzi M (2008) J. Mol. Struct. Theo-
chem 858:46
14. Ronchin L, Vavasori A (2009) J Mol Catal A Chem 313:22
15. Aricò F, Quartarone G, Rancan E, Ronchin L, Tundo P, Vavasori
A (2014) Catal Commun 49:47
16. Rancan E, Quartarone G, Ronchin L, Vavasori A (2015) Catal Lett
145:939
17. Zhang JS, Riaud WAK, Lu YC, Luo GS (2014) Catal. Lett
144:151
18. Zhang JS, Lu YC, Wang AK, Luo GS (2013) Ind Eng Chem Res
52:6377
19. Quartarone G, Ronchin L, Tosetto A, Vavasori A (2014) Appl
Catal A-Gen 475:169
20. Bianchini E, Pietrobon L, Ronchin L, Tortato C, Vavasori A
(2019) Appl Catal. A-Gen. 570:130
21. https://www.marketwatch.com/press-release/acetaminop
hen-market-forecast-to-grow-at-45-cagr-detailed-analy
sis- benef its- top- brands- busin ess- strat egies- and- regio
nal-demand-till-2025-2020-10-06
22. Horlenko T, Fritch J.R, Fruchey OS to Hoechst Celanese Corpora-
tion, US pat. 4954652 (1990).
Supplementary Information The online version contains supplemen-
23. Quartarone G, Rancan E, Ronchin L, Vavasori A (2014) Appl
Catal A-Gen 472:167
tary material available at https://doi.org/10.1007/s10562-021-03590-z.
24. Rancan E, Aricò F, Quartarone G, Ronchin L, Tundo P, Vavasori
A (2014) Catal Commun 54:11
Funding Open access funding provided by Università Ca’ Foscari Ven-
ezia within the CRUI-CARE Agreement.
25. Pietrobon L, Ronchin L, Sadraoui C, Pontello R, Tosetto C, Vava-
sori A (2020) Appl. Catal. A-Gen. 598:117570
26. Long LA, (2004) Process Saf. Prog. 114.
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27. H. Ritz, H. Fuchs, H. G. Perryman, “Hydroxylamine” in Ulmann’s
Encyclopedia of Industrial Chemistry, 18 (2000) 503–509, Wiley
on line eds.
28. Jones RN, Thorn GD (1949) Canadian J of Res 27:580
29. Marziano NC, Ronchin L, Tortato C, Tonon O, Bertani R (2004)
Int J Chem Kinet 36:417
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