Beckmann rearrangement of acetophenone oximes to the corresponding amides organo-catalyzed by trifluoroacetic acid for sustainable NSAIDs synthesis

Article abstract of DOI:10.1016/j.apcata.2013.12.026

The Beckmann rearrangement of acetophenone oximes to the corresponding amides (4-hydroxyacetophenone oxime to N-acetyl-4-hydroxyacetanilide and acetophenone oxime to N-phenylacetamide) is investigated by using trifluoroacetic acid (TFA) as catalyst. The reaction occurs either in the presence or in the absence of a suitable solvent. High selectivity and practically quantitative yield to amide is achieved in both cases at TFA/substrate > 3. Both TFA and the solvent (whenever present) could be easily reused by distillation since no protonation of amides occurs. The reaction proceeds via a multistep reaction path and the role of TFA is related not only to its acidity but also mainly to its ability on forming reactive trifluoroacetylated intermediates. In particular, the highly reactive trifluoroacetylated amide is actually the effective catalyst. Finally, a likely reaction path is proposed.

Full text of DOI:10.1016/j.apcata.2013.12.026

Applied Catalysis A: General 472 (2014) 167–177
Contents lists available at ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Beckmann rearrangement of acetophenone oximes to the
corresponding amides organo-catalyzed by trifluoroacetic
acid for sustainable NSAIDs synthesis
Giuseppe Quartarone, Elia Rancan, Lucio Ronchin∗, Andrea Vavasori
Department of Molecular Sciences and Nanosystems, University Ca’ Foscari of Venice, Dorsoduro 2137, 30123, Venezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The Beckmann rearrangement of acetophenone oximes to the corresponding amides (4-
hydroxyacetophenone oxime to N-acetyl-4-hydroxyacetanilide and acetophenone oxime to
N-phenylacetamide) is investigated by using trifluoroacetic acid (TFA) as catalyst. The reaction
occurs either in the presence or in the absence of a suitable solvent. High selectivity and practically
quantitative yield to amide is achieved in both cases at TFA/substrate > 3. Both TFA and the solvent
(whenever present) could be easily reused by distillation since no protonation of amides occurs. The
reaction proceeds via a multistep reaction path and the role of TFA is related not only to its acidity
but also mainly to its ability on forming reactive trifluoroacetylated intermediates. In particular, the
highly reactive trifluoroacetylated amide is actually the effective catalyst. Finally, a likely reaction path
is proposed.
Received 16 September 2013
Received in revised form
27 November 2013
Accepted 21 December 2013
Available online 28 December 2013
Keywords:
Trifluoroacetic acid
Organocatalysis
Beckmann rearrangement
Acetaminophen
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
Conversely, both the route via selective nitrobenzene hydro-
genation to 4-aminophenol and the Hoechst-Celanese process are
Acetanilide (N-phenylacetamide) and paracetamol or
acetaminophen (N-acetyl-4-aminophenol) are antipyretic–
analgesic drugs. Besides acetanilide has been employed in drug
formulations for long time, though, now for this use it is almost
completely substituted by acetaminophen [1–5]. In any case,
acetanilide is an important intermediate in the production of fine
chemicals, in fact, it is used as an inhibitor of peroxides, stabilizer
for cellulose ester varnishes, as an intermediate for the synthesis
of rubber accelerators, dye intermediate and as a precursor in
penicillin synthesis [5].
Acetaminophen production is in continuous growth and its
industrial synthesis is based on four different routes: (i) from phe-
nol, (ii) from chlorobenzene, (iii) from nitrobenzene and (iv) from
4-hydroxyacetophenone oxime (4-HAPO), the latter known also as
the Hoechst-Celanese process [2,3]. In the past, the first two pro-
cesses were predominant, while the last two have been evolving in
recent years [3]. From economical and environmental point of view
the first two show more concerns, due to the large coproduction of
unwanted byproducts (such as isomers and salts). In addition, the
processes are carried out in batch reactors, thus implying small
production with high costs.
continuous multistage plant developed for large productions [1–4].
These processes involve the use of acid catalysts and the plants in
operation are actually using mineral acids, which limit their sus-
tainability from both environmental and economical point of view
[4]. The latter, particularly, comprises several stages where acid cat-
alysts are involved: the Fries rearrangement of phenyl acetate, the
oximation of the 4-hydroxyacetophenone to 4-HAPO and finally
its Beckmann rearrangement to paracetamol [1–3]. Above all, Fries
and Beckmann rearrangement require strong acids and severe reac-
tion conditions [1–3]. Both the stages employ mineral acid and
inorganic bases each one with the necessary hold-up operation,
clearly their sustainability improvement passes through the use of
easily reusable acid catalytic system.
The studies related to the Beckmann rearrangement have been
particularly focused on the cyclohexanone oxime to ␧-caprolactam
conversion, since this reaction is of paramount importance for the
industry, being this lactam the key intermediate for nylon 6 pro-
duction [6–10]. A large number of papers dealing to the Beckmann
rearrangement of ketoximes are available in literature employ-
ing liquid and solid acid catalysts (both inorganic and organic)
[11–18], but few papers are specifically available on the Beckmann
rearrangement of the 4-hydroxy acetophenone oxime as interme-
diate for acetaminophen synthesis [14–17]. In patent literature the
most important application are referred to the Celanese process but
there are some patents claiming the Beckmann rearrangement of
ketoximes to the corresponding amides [2,3,19,20].
∗
Corresponding author.
E-mail address: ronchin@unive.it (L. Ronchin).
0926-860X/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.apcata.2013.12.026

168
G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
OH
OCOCF3
O
N
N
COCF3
N
O
-H2O
OH
CF3COOH
+
OCOCF3
O
N
N
COCF3
+
NH
N
+
Scheme 1. Schematic reaction mechanism of TFA catalyzed Beckmann rearrangement of cyclohexanone oxime to ␧-caprolactam see Ref. [28].
Among the liquid acids TFA appears to be really interesting
hydroxylamine hydrochloride 99%, dimethyl carbonate were
Aldrich products; (HPLC),
for synthetic purposes, because of its low boiling point (346 K),
which allows an easy recovery and recycling of the acid by dis-
tillation without products decomposition [21,22]. In addition, TFA
is non toxic, quite stable, its decomposition does not give harm-
ful products and it does not give accumulation phenomena in
the environment [23]. However, except the paper of Cossy and
coworkers, who employed TFA for the rearrangement of ketoxime
carbonate [24], TFA was not used for this reaction as a catalyst
and only in few cases it was employed in the solvent system
but not recognized as catalyst [25]. During the last 5 years our
research group has studied the Beckmann rearrangement of cyclo-
hexanone oxime to ␧-caprolactam in the presence of TFA as catalyst
[26–29]. For instance, we showed that TFA in CH3CN as a sol-
vent gives practically quantitative conversion with high selectivity
in the Beckmann rearrangement of cyclohexanone oxime to ␧-
caprolactam [27–29]. Furthermore, the solvent catalytic system
CH3CN-TFA is fully reusable because of the acidity of the TFA does
not allow the formation of the caprolactam salt, typically observed
with mineral acids, thus it does not need neutralization [26–29].
Those papers clearly evidenced that the reaction occurs via an
organocatalyzed path due to the formation of compounds involving
TFA esters [26–29]. The proposed reaction mechanism envisages
the formation of the oxime ester of the trifluoroacetic acid, which,
after rearrangement, forms a trifluoroacetyl acetamide. The latter
is the key intermediate of the catalysis being the trifluoroacetylat-
ing compound of the oxime, which continuously reforms the ester
sustaining the catalytic cycle (Scheme 1).
Very recently Luo and co-workers deposited a patent for the
synthesis of amides, based on the use of TFA-CH3CN system [30].
As a matter of fact, the application claims a procedure quite similar
to that proposed in our previous papers and the final results are
practically overlapping [26–30].
In this work we study TFA as catalyst for the Beckmann
rearrangement of aromatic ketoximes to the corresponding amides,
employing both APO and 4-HAPO as substrates and we show that
TFA acts in both cases as an organocatalyst. In addition, we inves-
tigate the influence of different solvents (also neat TFA) and of
the operative variables on reaction rate conversion and selectivity.
Finally, on the basis of the reactivity of the intermediates we pro-
pose a reaction mechanism, which explains the behaviors of both
the oximes.
4-hydroxiacethophenone ≥ 98%
dichloromethane, acetonitrile, nitroethane, were all HPLC
grade Fluka products. Dimethyl sulfoxide (DMSO) 99% and
1,2-dichloroethane 99% were ACS reagent Aldrich. Deuterated
chloroform, deuterium oxide and deuterated dimethyl sulfoxide
(DMSO-d6) were EurisoTop products.
2.2. Instruments
The gas-chromatograph (GC) Agilent model 6890, equipped
with a HP5, film thickness 2.65 ␮m, 30 m × 530 ␮m column; detec-
tor: flame ionization detector (FID); carrier gas: N2, 0.9 mL/min;
oven: 333–523 K (5 min) at 5 K/min was used mainly for the anal-
ysis of APO reactions.
The quantitative analyses of 4-HAPO rearrangement were car-
ried out exclusively by high performance liquid chromatography
(HPLC), because 4-HAPO and acetaminophen decompose into the
GC injector. The HPLC instrument employed was a Perkin Elmer
˚
binary LC pump 250 with phenomenex Luna, 5 ␮m C18 100 A, LC
column 300 mm × 4.6 mm (detector: Perkin Elmer LC 235 C Diode
Array, wavelengths: 255 nm and 220 nm; carrier: mix water – ace-
tonitrile with a concentration gradient 60% water (9 min), 50%
water (5 min) and 30% water (1 min)).
Despite of both APO and acetanilide are stable by GC analysis
the rearrangement was followed by using either GC or HPLC, since
intermediates appears to decompose by using both the techniques.
The gas-chromatograph coupled mass spectroscopy (GC-MS)
Agilent model 5975C interfaced with GC Agilent model 7890
equipped with a HP5 film thickness 0.5 ␮m, 30 m × 250 ␮m was
used throughout the experiments for checking reaction products.
The reaction carried out in the presence of H2SO4 and CH3SO3H
were analyzed after dilution with water and extraction with
dichloromethane, the rest were analyzed without any neutraliza-
tion.
The 1H NMR spectra were recorded on a Bruker AC 200 spec-
trometer operating at 200.13 MHz, the sample temperature was
maintained at 298 K. The reagent concentrations were chosen in
order to simulate the real catalytic conditions. All the chemical
shifts were referred to internal tetramethylsilane.
2.3. Ketoxime synthesis
2. Experimental
4-HAPO and APO were synthesized from the corresponding
ketone (4-hydroxyacetophenone and acetophenone) by follow-
ing the procedure described in literature [27,28]. In a typical
preparation, a flask equipment equipped with reflux condenser
was charged with 170 mL of water, 0.51 mol of hydroxylamine
hydrochloride, 0.81 mol of sodium acetate and 0.15 mol of 4-HAPO.
The reaction was heated at ca. 363 K for 1 h and then, after cooling,
2.1. Materials
All solvents and products were employed as received with-
out further purification. Acetophenone ≥ 98%, trifluoroacetic
acid 99%, trifluoroacetic anhydride > 99%, nitroethane 96% and

G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
169
AcP-TFA, 1H NMR ı 9.64 (s, 1H, OH), 7.45–7.32 (d, 2H), 6.70–6.65
(d, 2H), 1.97 (s, 3H).
the solid was filter and washed with a saturated solution of NaCl
and NaHCO3 at 273 K. The crude 4-HAPO was dissolved in water
and extracted with diethyl ether. After evaporation of the solvent
the solid was twice recrystallized with diethyl ether and hexane.
NMR assignments:
2.5. Beckmann rearrangement reactions
All the operations were carried out under nitrogen (charged at
atmospheric pressure) in a jacketed sealed glass reactor (10 mL)
at several temperatures and autogenous pressure. The course of
reactions was checked sampling the liquid phase by a syringe at
established intervals. All the analyses were carried out by GC and
GC–MS when APO was employed as substrate, while HPLC and
GC–MS were used when the substrate was 4-HAPO. The potential of
the method as an alternative synthetic route for obtaining different
amides has been tested on several oximes giving, in any case, high
yield in the corresponding amides (see supplementary materials).
In a typical experiment, a glass reactor was charged with
1.3 mmol of 4-HAPO, 9 mL of nitroethane and 12.5 mmol of TFA
under nitrogen. The reaction time was computed after the TFA
addition.
The first derivative at time 0 of the third order polynomial,
obtained by fitting the time decreasing concentration of 4-HAPO,
gives the overall initial reaction rate, thus allowing the control of
the influence of the operative variable on the reaction kinetics. In
this case substrate consumption and amide formation has been fol-
lowed by HPLC analysis since GC cannot be employed since either
4-HAPO or acetaminophen decompose in the GC injection system,
giving not reliable results in the quantitative analysis.
4-HAPO, white solid, m.p. 413-418 K, 1H NMR: (200 MHz,
(CD3)2SO), ı 10.84 (s, 1H, N OH), 9.60 (s, 1H, OH), 7.49–7.45 (d,
2H), 6.78–6.73 (d, 2H), 2.09 (s, 3H) [31];
APO, white solid, m.p. 331-333 K, 1H NMR: (200 MHz, CDCl3), ı
9.04 (br s, 1H, OH), 7.68–7.63 (m, 2H), 7.43–7.40 (m, 3H), 2.34 (s,
3H) [32].
2.4. Synthesis of O-trifluoroacetyl oximes ester, N-trifluoroacetyl
acetanilide, N-trifluoroacetyl 4-hydroxyacetanilide
An
attempt
to
obtain
O-trifluoroacetyl-4-hydroxy-
acetophenone oxime (4-HAPO-TFA) by following the procedure
reported for cyclohexanone oxime in previous papers does not give
satisfactorily results [27,28]. In fact, the formation of 4-HAPO-TFA
by reacting trifluoroacetic anhydride with 4-HAPO is not observed
since, the instantaneous rearrangement to acetaminophen is
observed also at 298 K.
The reactivity of trifluoroacetic anhydride with acetophe-
none oxime at 353 K gives in few minutes acetanilide but,
O-trifluoroacetyl acetophenone oxime (APO-TFA) is formed at
298 K by following the procedure reported for cyclohexanone
oxime in previous papers [27,28]. The reaction occurs almost quan-
titatively in various solvent in a typical preparation 25 mmol of
APO reacts with an equimolar amount of trifluoroacetic anhydride
in 3 mL of CH2Cl2. To avoid fast decomposition of the products,
APO-TFA is maintained in a DMSO solution in the presence of an
over-stoichiometric amount of trifluoroacetic anhydride (1.1 equiv.
with respect to APO-TFA). The product is identified by 1H NMR,
GC–MS and HPLC (see supplementary materials).
The initial rate of APO rearrangement was measured by the first
derivative at time 0 of the third order polynomial obtained by fitting
the time vs. acetanilide formation data. The different methods in the
calculation of the initial rate of reaction for the two substrate is due
the fact that APO shows a complex reaction path, then acetanilide
formation appears to be a simple and reproducible parameter for
measuring the overall reaction rate.
2.6. Products, solvent and catalyst recovery
N-Trifluoroacetyl-4-hydroxyacetanilide
(AcP-TFA)
or
N-trifluoroacetyl-acetanilide (AcA-TFA) are obtained by triflu-
oroacetylation of acetaminophen or acetanilide in acetonitrile,
the products are identified via GC–MS and NMR (see supplemen-
tary materials). In a typical preparation 26 mmol of paracetamol
was dissolved with 3 mL of acetonitrile and added 26 mmol of
trifluoroacetic anhydride in a glass flask, then the reaction was
stirred for 1 h at 298 K. The solvent was eliminated under vacuum
by a rotary evaporator at 298 K; a deliquescent white solid was
obtained and analyzed by HPLC, GC–MS and NMR (see supple-
mentary materials). Analogous procedure was followed to prepare
N-trifluoroacetyl acetanilide (see supplementary materials). It
is noteworthy that all the compounds are moisture sensitive.
To avoid fast decomposition of the products, both AcP-TFA and
AcA-TFA are maintained in a DMSO or CH3CN solution in the
presence of an over-stoichiometric amount of TFA (1.1 equiv. with
respect to AcP-TFA or AcA-TFA).
The reacted mixture is transferred to a mini distillation appara-
tus equipped with membrane pump, operating at 130 Pa and with a
condenser chilled at 273 K with a circulating thermostat. The mix-
ture is heated at 353 K, than the solvent quickly distils. The solvent
recovered is over 95% of the initial solvent, the rest is in the distil-
lation apparatus. The residue is recovered and the isolated yield of
acetanilide and acetaminophen are ca. 90–95%.
3. Results and discussion
3.1. Influence of the solvent on the Beckmann rearrangement of
4-HAPO and APO catalyzed by TFA
Table 1 reports the influence of the solvent on the Beckmann
rearrangement reaction of 4-HAPO and APO after 2 h of reaction.
It is noteworthy that conversions are close to completeness in
the presence of various solvents, in some cases the reaction is prac-
tically quantitative to the desired amide, except entries 4, 6 and
8 that are carried out in the presence of ethanol, DMC and DMSO,
respectively. As regard the reactivity in ethanol, the behavior is
expected, since TFA reacts almost instantly with the alcohol to
give ethyl trifluoroacetate, thus subtracting the acid to the reac-
tion environment. In the presence of DMC the reaction does not
proceed but no byproducts were observed. This strong solvent
effect is generally related to a stabilization of a charged inter-
mediate, whose stability increases the activation energy of the
overall process [35]. This strong solvent interaction inhibits also
all the reactions involved in the process (oxime hydrolysis and/or
NMR assignments:
APO-TFA, 1H NMR (200 MHz, CDCl3),
7.54–7.26 (m, 3H), 2.51 (s, 3H);
ı 7.75–7.70 (m, 2H),
acetanilide, white solid m.p. 385–389 K, 1H NMR (200 MHz, CDCl3),
ı 8.19 (br s, 1NH), 7.55–7.51 (m, 2H), 7.33–7.25 (m, 2H), 7.13–7.06
(m, 1H), 2.15 (s, 3H) [33];
AcA-TFA, 1H NMR (200 MHz, CDCl3),
7.25–7.20 (m, 2H), 2.55 (s, 3H);
ı 7.52–7.47 (m, 3H),
acetaminophen, white solid m.p. 440–443 K 1H NMR ((CD3)2SO,
200 MHz), ı 9.63 (s, 1H, OH), 9.12 (br s, 1H, NH), 7.36–7.31 (d,
2H), 6.69–6.65 (d, 2H), 1.98 (s, 3H) [34];

170
G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
Table 1
Beckmann rearrangement of 4-HAPO and APO catalyzed by TFA in the presence of various solvent.
Entry
Solvent
4-HAPO
APO
Conv.a (%)
Select.b (%)
T (K)
Conv.a (%)
Select.c (%)
T (K)
1
2
3
4
5
6
7
8
9
Acetonitrile
Nitromethane
Nitroethane
Ethanol
1,2-Dichloroethane
DMC
DMSO
Chloroform
TFA
99
>99
>99
99
99
>99
/
96
/
343
343
343
343
343
343
343
343
343
343
343
>99
>99
>99
60.2d
99
>99
/
95
/
358
358
358
358
358
358
358
358
358
358
358
e
e
/
/
97
<1
/
96
97
98
99
96
<1
/
96
>99
99
99
/
/
96
96
99
99
98
99
99
99
10
11
CH3SO3H
H2SO4 75%
Run condition: molar ratio TFA/substrate = 10, TFA = 13.2 mmol, total volume = 10.8 mL, time of reaction 120 min.
a
Oxime conversion.
Selectivity to acetaminophen.
Selectivity to acetanilide.
Formation of APO-TFA are observed; after 18 h of reaction acetanilide yield 99%.
b
c
d
e
TFA is converted quantitatively to its ethyl ester and reaction does not proceed further.
esterification). In fact, these reactions are observed for APO (entry 1)
as well as for cyclohexanone oxime rearrangement in TFA–CH3CN
[26–29]. Correspondingly, in DMSO (entry 7), the reaction does not
proceed, likely for a similar solvent reason [35]. Entry 8 shows high
conversion and selectivity for both 4-HAPO and APO in chloroform
as the solvent.
Reactions carried out in neat TFA (entry 9) show high conversion
and selectivity to the desired amide for either 4-HAPO or APO.
Entries 10 and 11 show the reactivity in CH3SO3H and H2SO4
70%, as expected in both cases high conversion and selectiv-
ity are achieved but dilution in water and extraction with
dichloromethane needs to recover the products.
The procedure has also been tested on several ketoximes and
aldoximes giving high yield in the desired amides, some prelim-
inary results are available on supplementary materials but this is
beyond the scope of the present research and further investigations
are in course.
The comparison of the two plots of Fig. 1 shows apparently two
completely different trends. The 4-HAPO rearrangement shows the
disappearing of the oxime with the concomitant increase of the rel-
ative amide (acetaminophen). On the contrary, the rearrangement
of APO shows a complex reaction pattern, in which is evidenced
that part of the starting oxime is transformed almost immediately
in various intermediates after the addition of the TFA. Furthermore,
acetanilide formation presents an induction period; this suggests
that the formation of a catalytically active intermediate requires a
certain time to reach the minimum concentration for starting the
catalysis of the rearrangement to acetanilide. Such an induction
period is temperature dependant (see supplementary materials)
and decreases as temperature raises. The intermediate of Fig. 1(b)
has been identified (GC–MS, NMR and compared with a standard
see supplementary materials) as APO-TFA and AcA-TFA, while ace-
tophenone derive from APO hydrolysis due to the reaction of the
protonated form of APO (APO pKa = 2.52, TFA pKa ≈ 0.47) with the
water deriving from the formation of the APO-TFA (esterification),
or from a secondary reaction path already described in a previous
paper [27–29,36–38].
3.2. Time vs. concentrations profile of the TFA catalyzed
Beckmann rearrangement in nitroethane as a solvent
This class of products, suggests a reaction path for the APO
Beckmann rearrangement, similar to that proposed for cyclohex-
anone oxime [27,28]. On the contrary, the time vs. concentration
profile of the 4-HAPO rearrangement would suggest a Brønsted
Fig. 1 shows the time vs. concentrations profile of the Beckmann
rearrangement of 4-HAPO and APO catalyzed by TFA in nitroethane
as a solvent.
a
b
100
75
50
25
0
100
75
50
25
0
0
50
100
150
200
250
300
350
0
20
40
60
80
Time, (min)
Time, (min)
Fig. 1. Time vs. concentrations profile of the Beckmann rearrangement of 4-HAPO (a) and APO (b) in nitroethane. Run conditions: reaction temperature 343 K, molar ratio
TFA/substrate = 10, nitroethane/substrate = 100, TFA = 13.2 mmol (14 mmol for APO). In (a): (ꢀ) = 4-HAPO, (᭹) = AcP; in (b): (ꢀ) = APO, (ꢁ) = acetophenone, (ꢀ) = APO-TFA,
(ꢂ) = AcA-TFA, (᭹) = acetanilide.

G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
171
TC = -20 kcal mol-1
100
75
50
25
0
-0.008
-0.010
-0.012
-0.014
-0.016
-0.018
TC = -32 kcal mol-1
TC = -53 kcal mol-1
0
50
100
150
200
250
300
350
0.00280 0.00285 0.00290 0.00295 0.00300 0.00305 0.00310
T-1, ( K-1)
Time, (minutes)
Fig. 2. Time vs. concentrations profile of the Beckmann rearrangement of APO in
nitroethane by using GC analysis. Run conditions: reaction temperature 353 K, molar
ratio TFA/substrate = 12, nitroethane/substrate = 100, TFA = 14.0 mmol; (ꢀ) = APO,
(ꢁ) = acetophenone, (᭹) = acetanilide, (ꢁ) = acetanilide GC.
Fig. 3. Arrhenius plot of initial rate from Beckmann rearrangement from
4-HAPO in nitroethane. Run conditions: molar ratio TFA/substrate = 10,
nitroethane/substrate = 100, TFA = 13.2 mmol.
acid catalyzed rearrangement similar to that observed in mineral
acid [38–41]. Nevertheless, this marked difference in the reaction
path between APO and 4-HAPO, evidenced in Fig. 1 could be only
apparent, because of the different method of analysis employed for
the two substrates (GC and HPLC, respectively). In fact, the need
of using HPLC for analyzing the samples of reaction of 4-HAPO
rearrangement may cause the hydrolysis of the intermediates,
which, on the contrary, are actually present into the reaction mix-
ture. This is demonstrated by following 4-HAPO rearrangement via
NMR in CDCl3, the spectra show complex reaction pattern, where
several intermediates are observed, but an unambiguous identifi-
cation of the intermediates is not possible (see supplementary). A
further hint that the lack of the intermediates of the time vs. con-
centrations profile of 4-HAPO rearrangement is due to an analytical
problem is evident by noting in Fig. 2 (compare with Fig. 1(b)) that
the time vs. profile of APO rearrangement is different if the reaction
course is followed by HPLC or by GC. As a matter of fact, the various
intermediates, evidenced by GC analysis disappear. Fig. 1(b) shows
the formation of AcA-TFA, immediately after the addition of TFA
thus suggesting a fast rearrangement of APO-TFA.
that a precise quantification of reaction intermediates cannot be
obtained, since thermal rearrangement and hydrolysis alter signif-
icantly their distribution vs. time. This behavior suggests that the
formation of the trifluoroacetylated-amide intermediate is the key
step in the rearrangement of both oximes in agreement with our
previous investigation [26–29].
In addition, the reactivity of the trifluoroacetylated amides
allows products recovery without work-up operations, which are
conversely indispensable in the presence of mineral acids [26–29].
3.3. Effect of temperature on the initial rate of Beckmann
rearrangement in nitroethane as a solvent
The effect of the temperature on initial rates of rearrangement
of 4-HAPO is reported in Fig. 3. The Arrhenius plot of 4-HAPO
rearrangement (Fig. 3) shows a noticeable non linear trend, thus
suggesting a complex reaction path, which is in agreement with
the multistep mechanism proposed in the previous section. From
an estimate of the temperature coefficient (TC), calculated by divid-
ing in zones the curve of the Arrhenius plot, it appears values of TC
ranging from 20 to 50 kcal mol−1. This confirms that several stages
influence the overall kinetics, thus the variation of temperature
causes the changes of the activation energy of the rate determining
step.
At difference of what observed for 4-HAPO, the initial rate of
the Beckmann rearrangement of APO is linear (see supplementary
materials). Apparently this disagrees with the results of Fig. 1(b),
which shows the formation of several intermediates. The value of
the TC of about 20 kcal mol−1 is similar to that measured for 4-HAPO
at higher temperatures and is practically the same with respect to
that measured in mineral acid [38–41].
In order to highlight this behaviors the reactivity of reagents
and intermediates with oximes, water and their stability under
different conditions are reported in Table 2.
The trifluoroacetylation of both the molecules occurs easily
with trifluoroacetic anhydride. In fact, the anhydride reacts with
4-HAPO at 298 K giving several compounds, whose equilibria after
dilution give acetaminophen quantitatively (see supplementary
materials). In contrast, APO reacts with trifluoroacetic anhydride
giving APO-TFA, which is stable at 298 K, but it rearranges at
343 K in the presence of TFA. In the gas phase, into the GC injec-
tor, APO-TFA rearranges promptly to AcA-TFA (yield 70%), thus
explaining the instantaneous formation of AcP-TFA observed in
Fig. 1(b). APO-TFA, AcP-TFA and AcA-TFA are moisture sensitive
giving fast hydrolysis to APO and to the corresponding amides and
releasing TFA. In the absence of water, AcP-TFA and AcA-TFA react
almost quantitatively with APO to APO-TFA and/or to acetanilide
and acetaminophen. Furthermore, AcP-TFA and AcA-TFA in the
presence of 4-HAPO mediate its rearrangement to acetaminophen
also at 298 K (see Table 2). This explains the trend of Fig. 2,
where no intermediates are observed but only APO consumption
and acetanilide formation due to the hydrolysis of the interme-
diates during HPLC analysis. Starting from these results it is clear
3.4. Effect of substrate concentration on the initial rate of
Beckmann rearrangement in nitroethane as a solvent
Fig. 4 reports the influence of the substrate concentration on
the initial rate of Beckmann rearrangement of 4-HAPO and APO.
As expected in both cases, the initial rate of reaction increases as
substrate concentration raise. A power low equation rate satisfac-
torily fit experimental data because of the linearity of the double
logarithmic plot (see supplementary materials) and the calculated

172
G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
Table 2
Stability of the reagents and intermediates after 60 min of reactions under various conditions.
Compound tested
Stability under various conditions
Reagent
Liquid 298 K
Yield %
Liquid 343 K
Gas GC 533 K
APO 343 K
4-HAPO 343 K
H2O 298 K
4-HAPO
APO
4-HAPO-TFA
APO-TFA
AcP-TFA
AcA-TFA
NR
NR
Re = 100
NR
NR
Est/Rea
Est/30
Re = 100
Re = 30
NR
Decb
NR
/
/
/
/
/
/
/
/
Hyc/Re = 1/2
Hyc = 1
Decb
Re = 70
Decb
NR
/
Hy = 100d
Hy = 100e
Hy = 100e
Ex/Re = 100/30
Ex = 100
Ex/Re = 100/40
Ex/Re = 100/40
NR
NR
Run conditions: solvent CH3CN, reaction volume 10 mL, TFA concentration 0.1 mol L−1, TFA/substrate = 1, substrate/reagent = 1.
Est = esterification, Gas GC = GC injector, Re = rearrangement, Dec = decomposition, NR = no reaction, Ex = exchange, Hy = hydrolysis.
a
Via NMR.
b
Traces of trifluoroacetylated compounds are observed but extensive decomposition occurs due to the poor thermal stability of phenols and aminophenols.
c
d
e
Hydrolysis to ketone.
Hydrolysis to oxime.
Hydrolysis to amide
concentrations higher than 2 mol L−1, the rate of rearrangement
of 4-HAPO reaches a plateau and after 2.5 mol L−1 also a slight
decrease can be noted. Analogous trend is observed also for APO,
with a constant increase till 3.2 mol L−1, at higher concentration
two phases is observed. It is likely that, as already observed
for the Beckmann rearrangement of cyclohexanone oxime in
TFA–CH3CN, protonation, esterification and exchange between the
trifluoroacetylated amide and the starting oxime, are all reactions
affecting the overall reaction rate [26–29].
reaction orders are 0.7 and 0.6 for 4-HAPO and APO, respectively. A
non integer reaction order suggests that there are some steps that
influence the rate determining step of the reaction [42,43]. This is
evident for the rearrangement of APO, whose time vs. concentra-
tion profile (Fig. 1(b)) shows some intermediates. For instance, the
formation of APO-TFA, which is an ester, is a step whose contribu-
tion easily explains a non integer reaction order [42,43]. It is likely
that also for 4-HAPO rearrangement the kinetics should be influ-
enced by analogous esterification and protonation equilibria, thus
explaining the non integer reaction order and the variation of the
TC with temperature.
3.6. Beckmann rearrangement in TFA as catalyst and solvent
3.5. Influence of TFA on the initial rate of Beckmann
rearrangement in nitroethane as a solvent
Fig. 6 shows the time vs. concentration profiles regarding to the
Beckmann rearrangement of 4-HAPO and APO, respectively, cat-
alyzed by neat TFA, which acts also as the solvent. Both reaction
profiles are similar to those observed in the presence of nitroethane
as a solvent (see Fig. 1), except the absence of acetophenone as
byproduct, for the rearrangement of APO, which causes a further
increase of the selectivity toward the acetanilide (see Fig. 6(b)).
The same behavior of the reaction carried out in the presence of
nitroethane (Fig. 2) is observed by analyzing the samples via HPLC
(see supplementary) in which no intermediates are observed for
APO rearrangement. This is in agreement with what already dis-
cussed in Section 3.2 suggesting that HPLC analysis causes the
hydrolysis of the trifluoroacetylated intermediates (4-HAPO-TFA
and AcP-TFA) also in the case of 4-HAPO.
In Table 3 the influence of the TFA/substrate ratio on conversion
and selectivity after 18 h of reaction is reported. It is noteworthy
that at a ratio higher than 3 the conversion is practically quantita-
tive and selectivity is as high as 95% in the desired amide and only
at TFA/substrate ratio of 1 ketone formation occurs noticeably. The
reason of such a behavior is likely due to the esterification equilibria
of the oxime, which is favored at the highest TFA/substrate.
In Fig. 5 the trend of the initial rate of rearrangement of 4-HAPO
and APO vs. the concentration of TFA is reported.
In both cases the trend of the initial rate of rearrangement
increases with respect to TFA concentration up to 2 mol L−1. At TFA
Fig. 4. Influence of 4-HAPO (a) and APO (b) concentration on the initial rate of Beckmann rearrangement of 4-HAPO in nitroethane. Run conditions: reaction temperature
343 K, molar ratio nitroethane/TFA = 10, TFA = 13.2 mmol (14 mmol for APO).

G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
173
Table 3
Influence of the TFA/substrate ratio.
Entry
TFA/substrate
4-HAPO
APO
Conv.a (%)
Selectivity (%)
Amide
Conv.a (%)
Selectivity (%)
Amide
Ketone
Othersb
Ketone
Othersc
1
2
3
4
5
6
1
1.5
2
3
5
64
90
99
99
99
99
29
51
76
95
98
99
70
31
14
3
/
/
1
18
10
2
2
1
55
84
91
99
99
99
5
27
46
94
96
98
75
60
20
3
/
/
20
13
14
3
3
2
10
Run conditions: solvent CH3CH2NO2, reaction volume 10 mL, TFA concentration 0.1 mol L−1, T = 353 K, time of reaction 18 h.
a
Oxime conversion.
Condensation products.
Others are mainly trifluoroacetylated amide and ketoxime.
b
c
3.7. Effect of temperature on initial rate of Beckmann
rearrangement in TFA
nitroethane as a solvent, this behavior suggests a complex reaction
path, where several stages in stationary state are involved. The non
homogeneous values of the TC for APO rearrangement are further
evidences that the reaction is multistep with equilibria [42,43].
The value of TC for the rearrangement of 4-HAPO in neat TFA is
lower than that observed in the presence of nitroethane, suggest-
ing a stabilization effect of the activated state in the presence of
neat TFA. The TC for APO rearrangement is practically the same
The trend of the Arrhenius plot of the initial rate of
rearrangement of 4-HAPO and APO are similar of those obtained
in nitroethane (see supplementary materials), with a non constant
value of the TC for 4-HAPO comprised between 7 and 30 kcal mol−1
.
As already pointed out for the reaction carried in the presence of
Fig. 5. Influence of TFA concentration on the initial rate of Beckmann rearrangement of 4-HAPO (a) and APO (b) in nitroethane as a solvent. Run conditions: reaction
temperature 363 K, molar ratio nitroethane/TFA = 10, nitroethane/substrate = 100, TFA = 13.2 mmol (14.0 mmol for APO), molar ratio nitroethane/substrate = 100.
a
b
100
75
50
25
0
100
75
50
25
0
0
50
100
150
200
250
0
25
50
75
100
125
Time, (min)
Time, (min)
Fig. 6. Time vs. concentrations profile of the Beckmann rearrangement of 4-HAPO (a) and APO (b) in neat TFA. Run conditions: reaction temperature 343 K, molar ratio
TFA/substrate = 10, TFA = 33.1 mmol. In (a): (ꢀ) = 4-HAPO, (᭹) = AcP; in (b): (ꢀ) = APO, (ꢂ) = AcA-TFA, (ꢀ) = APO-TFA, (᭹) = acetanilide.

174
G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
Table 4
Influence of the TFA/substrate ratio.
Entry
TFA/substrate
4-HAPO
APO
Conv.a (%)
Selectivity (%)
Amide
Conv.a (%)
Selectivity (%)
Amide
Ketone
Othersb
Ketone
Othersc
1
2
3
4
5
6
1
1.5
2
3
5
66
99
99
99
99
99
70
85
94
96
98
99
29
3
2
2
/
1
12
4
2
2
56
99
99
99
99
99
8
58
93
95
98
99
16
2
2
2
/
62
40
5
2
2
10
/
1
/
1
Run conditions: substrate 1 mmol T = 353 K, time of reaction 18 h.
a
Oxime conversion.
Condensation products.
Others are mainly trifluoroacetylated amide and ketoxime.
b
c
of that measured in the presence of nitroethane as a solvent
(TF = 21 kcal mol−1).
3.9. Hypothesis on reaction mechanism and reactivity of the
intermediates
The reaction path for APO rearrangement is clearly via the
intermediates APO-TFA and AcA-TFA, which are evidenced in the
reaction mixture (Figs. 1(b) and 6(b)) and isolated (see supple-
mentary). In additions, the reactivity of the intermediates suggests
the active role of TFA as organocatalyst being the essential com-
ponent in their formation and not only the proton donor. In any
case, a reaction path via a purely Brønsted acid catalysis cannot
be completely ruled out being the oxime easily protonated in this
range of acidity [38,39]. In addition, the FT-IR spectra of the 2,4,6-
trimethylacetophenone oxime in the presence of TFA at 298 K do
not show formation of nitrilium ion (see spectra in supplementary
materials), which is observed in strong mineral acid under the same
conditions with this oxime [38–41].
The induction period in the acetanilide formation is a fur-
ther evidence that a Brønsted acid catalysis for APO Beckmann
rearrangement is poorly probable. As a matter of fact, protonation
is a fast reaction, and then it does not explain the induction period
observed in acetanilide formation. On the contrary, the explanation
of an induction period could be connected with the formation of a
long living intermediate, which retards the conversion to the final
product [42,43]. Another possible explanation of the long induc-
tion period could be related to an autocatalytic phenomena [42,43].
For these reasons it is more likely that the induction period in
acetanilide formation is caused by the needs of forming AcA-TFA,
which is the intermediate that close the catalytic cycle (Scheme 2).
These evidences suggest a reaction mechanism (Scheme 2), which
3.8. Effect of substrate concentration on the initial rate of
Beckmann rearrangement in TFA
In Table 4 the influence of the TFA/substrate ratio on conversion
and selectivity after 18 h of reaction is reported. As in the presence
of nitroethane as a solvent at a ratio higher than 3 the conversion
is practically quantitative and with amides selectivity higher than
95%.
In Fig. 7 are reported the initial rate of 4-HAPO and APO. Fig. 7
shows in both cases an increasing trend of the initial rate of
rearrangement as the concentration of substrate raise. As regard
4-HAPO, the power law kinetics gives a good fit of the experimen-
tal data with a reaction order of 1.72 (see supplementary materials),
at difference of what observed in nitroethane as a solvent, where
the kinetics shows a reaction order lower than 1 (0.72). This behav-
ior is likely due to the solvent effect on the equilibria (for instance
protonation and/or esterification of oxime) in which the substrate
is involved, and not from a change of reaction mechanism for the
absence of the solvent [42,43].
Fig. 7(b) reports the trend of initial rate of rearrangement vs.
APO initial concentration; the power law kinetics fits the data giv-
ing an overall reaction order of about 1.78, which is also in this
case greater than 1. In this way, the reaction order is increased of
an unity compared to that measured in the reaction carried out in
nitroethane. Also in this case, a solvent effect is likely acting on the
various equilibria present in the reaction environment [35,42,43].
Fig. 7. Influence of 4-HAPO (a) and APO (b) concentration on the initial rate of rearrangement. Run condition: reaction temperature 343 K, TFA = 33.1 mmol.

G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
175
Scheme 2. Mechanism of the Beckmann rearrangement catalyzed by TFA.
is in agreement with that proposed for the cyclohexanone oxime
and including the following steps:
relating the transformation of 4-HAPO in trifluoroacetic anhydride
to AcP-TFA.
At difference of APO-TFA, we are not able to isolate 4-HAPO-
TFA (see Table 2), but the NMR spectra of the reaction of 4-HAPO
with trifluoroacetic anhydride at 298 K in DMSO gives some use-
ful information. For instance (see spectra 3–4), in the presence of
0.3 and 0.7 equiv. of trifluoroacetic anhydride (with respect to the
4-HAPO) it appears two species: AcP-TFA and the second one has
the same spectrum of the 4-HAPO in the presence of TFA (com-
pare with spectrum 2). Increasing to 0.9 equiv. of trifluoroacetic
anhydride, the signal of the AcP-TFA remains practically the only
one (compare with spectra 5 and 6). It is noteworthy to remem-
ber that the reaction does not occur in the presence of TFA and
in DMSO as a solvent (see Table 1), but is fast in the presence of
trifluoroacetic anhydride at 298 K, too. It is likely that a charged
intermediate is not necessary, in the presence of trifluoroacetic
anhydride, since it is a quite strong neutral electrophile whose reac-
tivity is less influenced by solvent polarity [35]. This behavior is
in agreement with the formation of a neutral intermediate such as
the ester (for instance APO-TFA and/or 4-HAPO-TFA), which under-
goes rearrangement without the involvement of an acid catalysis.
The presence of the strongly solvating DMSO or DMC stabilizes the
protonated oximes, which are not involved in the catalytic process.
The complex behavior of the TC is a clear evidence that the 4-HAPO
rearrangement follows a multistep mechanism, since this behav-
ior cannot be explained merely in terms of a Brønsted acid catalysis
[42,43]. The multistep organocatalyzed reaction mechanism, which
is evident for APO, explains without contradictions also the reactiv-
ity of 4-HAPO, of AcP-TFA and the complex behavior of the TC, for
(i) APO reacts with TFA to give the ester APO-TFA (equilib-
rium) [26–29]. This compound has a highly electron deficient
nitrogen atom, thus allowing easy Beckmann rearrangement
[38–41].
(ii) APO-TFA rearranges to AcA-TFA (irreversible) [38–41].
(iii) AcA-TFA reacts with APO to give acetanilide plus APO-TFA and
with water to give TFA plus acetanilide.
Unfortunately, it is not possible a straight parallelism between
the reactivity of 4-HAPO with that of APO, since the time vs.
concentration profile of the former present apparently no evi-
dent intermediates, then it does not allow any direct comparison.
However, as already pointed out in Section 3.2, the absence of inter-
mediates is due to their hydrolysis during samples preparation for
carrying out HPLC analysis. 4-HAPO rearrangement has been fol-
lowed by NMR in CDCl3 and it shows complex reaction pattern,
where several intermediates are observed, but a sure identification
of these intermediates is not possible (see supplementary materi-
als). In addition, the reactivity of APO and 4-HAPO with AcP-TFA
gives almost instantly at room temperature exchange reaction to
acetanilide plus acetaminophen and a further rearrangement to
acetaminophen is observed for 4-HAPO (see Table 2). Starting from
these evidences, even though, AcP-TFA has not be directly observed
during the reaction, it is likely that AcP-TFA could be involved in
4-HAPO rearrangement, thus suggesting to follow the same mecha-
nism proposed for APO (Scheme 2). Fig. 8 reports some NMR spectra

176
G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
Fig. 8. 1H NMR ((CD3)2SO, 200 MHz) spectra relating the transformation of 4-HAPO in the presence of trifluoroacetic anhydride (ATF) and TFA and the comparison with
AcP-TFA and acetaminophen (AcP) in the presence of TFA.
this reasons, it appears more likely than the Brønsted acid catalyzed
path.
giving finally the desired amide. This reaction mechanism seems to
be quite evident for APO, but by taking into account the behavior
of the TC, the reactivity of 4-HAPO in trifluoroacetic anhydride and
that of AcP-TFA, such pathway could be reasonably extended also
to acetaminophen formation.
4. Conclusions
The use of TFA in the synthesis of paracetamol and acetanilide
with respect to the traditional processes which employ mineral
acid or thionyl chloride presents the following benefits:
Acknowledgements
Financial support by Ca’ Foscari University of Venice is gratefully
acknowledged (ADIR fund 2011). A special thank to Mr. Claudio
Tortato for the helpful discussions.
i. lower toxicity;
ii. easier separation of reaction mixture and recyclable solvent;
iii. TFA may be used pure or in combination with other aqueous or
not aqueous solvent.
Appendix A. Supplementary data
Besides, the new features of the synthetic procedure, we pro-
pose a reaction pathway where TFA acts as an organocatalyst by
forming the oxime ester, which rearrange to the corresponding tri-
fluoroacetyl amide, being the latter, in turn, responsible for the
trifluoroacetylation of the oxime, closing the catalytic cycle and
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.apcata.
2013.12.026.

G. Quartarone et al. / Applied Catalysis A: General 472 (2014) 167–177
177
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