Ammonolysis of anilides promoted by ethylene glycol and phosphoric acid

Article abstract of DOI:10.1039/c4ra09065a

Ethylene glycol (EG) and phosphoric acid have been found to promote the ammonolysis of a variety of diverse anilides as well as N-aryl carbamate, phthalimide, and urea substrates in the absence of transition metals or other Lewis acid promoters.

Full text of DOI:10.1039/c4ra09065a

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Ammonolysis of anilides promoted by ethylene
glycol and phosphoric acid†
Cite this: RSC Adv., 2014, 4, 46840
*
*
Nickeisha A. Stephenson, Samuel H. Gellman and Shannon S. Stahl
Received 22nd August 2014
Accepted 10th September 2014
DOI: 10.1039/c4ra09065a
www.rsc.org/advances
Ethylene glycol (EG) and phosphoric acid have been found to promote
Early in this study, we identied two precedents for the direct
the ammonolysis of a variety of diverse anilides as well as N-aryl ammonolysis of amides: (1) the depolymerization of nylon,
carbamate, phthalimide, and urea substrates in the absence of tran- which typically features Lewis acidic metal salts or heteroge-
neous catalysts at high temperatures (>250 C)5 and (2) a 1926
ꢀ
sition metals or other Lewis acid promoters.
PhD thesis describing the ammonolysis of acetanilide with 10
The prominence of carboxamides in synthetic and naturally
occurring molecules and polymers can be attributed, at least in
part, to the robust nature of the amide functional group. Ami-
nolysis and transamidation reactions [eqn (1)] represent an
interesting class of approximately thermoneutral exchange reac-
tions that could have utility in dynamic covalent chemistry or
synthetic applications. In 2003, we reported a catalytic method
capable of equilibrating amines and secondary carboxamides.1,2
In subsequent years, we3 and others4 expanded upon these results
by identifying new classes of catalysts, improving catalytic activity,
and identifying new methods that utilize this reactivity. Despite
these advances, ammonia has not been shown to serve as an
effective reaction partner. The ammonolysis of amides [eqn (2)]
would be useful for the conversion of secondary or tertiary amides
to primary amides or the deprotection of acylated primary or
secondary amines. Such methods also provide the basis for the
recycling of polyamides, such as nylon and Kevlar.5 Here, we
report a protocol for the ammonolysis of anilides that is strongly
promoted by phosphoric acid in ethylene glycol as a solvent.
atm NH3 and 1.3 equiv. NH4Cl at 275 C.6 In order to pursue
ꢀ
more appealing reaction conditions, we selected 2-phenyl-
acetanilide as a substrate. Preliminary studies revealed that our
previously reported metal-catalyzed transamidation protocols
were not effective with ammonia as the substrate (see below). An
alternative strategy, however, was suggested from studies of the
ammonolysis of esters, in which water and diols were found to
promote the reaction.7 The reactivity of 2-phenylacetanilide
(1)
(2)
Department of Chemistry, University of Wisconsin – Madison, 1101 University Avenue,
Madison, WI 53706-1322, USA
Fig. 1 Yield of aniline (black bars) and 2-phenylacetamide (striped
bars) obtained from the ammonolysis of 2-phenylacetanilide (0.5
mmol) in various solvents (5 mL). TFE ¼ trifluoroethanol, HFiPr ¼
1,1,1,3,3,3 hexafluoro-2-propanol.
† Electronic supplementary information (ESI) available: Details of experimental
protocols, reaction optimization data, and substrate characterization data. See
DOI: 10.1039/c4ra09065a
46840 | RSC Adv., 2014, 4, 46840–46843
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with ammonia (7 atm) was tested in the presence of a number of Fig. 1. A variety of Lewis acids (20 mol%) were tested as possible
different solvents, including water, glycerol, diols, and simple catalysts for the ammonolysis of heptanilide in EG (Fig. 2A). In
alcohols (Fig. 1). Yields of both products were analysed by gas these reactions, a 5 M solution of NH3 in EG was used to
chromatography. The reaction in water afforded good yields of enhance the operational simplicity of the method relative to
aniline, but only a few percent of phenylacetamide was adding NH3 at high pressure. Numerous reactions containing
obtained. Phenylacetic acid was generated as the other major Lewis acids performed signicantly better than the reaction
product (ꢁ50%). In contrast, good yields of both aniline and without a Lewis acid. The combination of NH3 and EG with
2-phenylacetamide were obtained in glycerol and ethylene Lewis acids could generate ammonium salts that serve as
glycol. Various other a,u-diols showed good results, but led to Brønsted acid catalysts.8 To test this possibility, we evaluated a
lower yields than with glycerol or ethylene glycol (EG). Hexa- number of different ammonium salts and other Brønsted acids.
uoroisopropanol (HFiPr) was the only mono-alcohol solvent Phosphoric acid and mono- and dibasic phosphoric acid salts
that led to good reactivity, presumably reecting its ability to were especially effective in promoting the desired reactivity
promote the reaction via hydrogen bond donation. DMSO was (Fig. 2B).
uniquely effective among aprotic solvents, which suggests that
The low cost and ease of working with H3PO4 prompted us to
solvent polarity could play a role in this reactivity. Poor reactivity continue with this catalyst/promoter. Lower ammonia
was observed in toluene, simple alcohols or ethers. Overall,
glycerol led to the best results; however, high viscosity makes
glycerol inconvenient, and subsequent ammonolysis reactions
were therefore carried out in EG.
Table 1 Ammonolysis of heptanamidesa
The reactivity of heptanilide was then tested, but only 51%
yields of aniline and heptanamide were obtained when the
ammonolysis was carried out in EG under the conditions of
Percent yield
Entry
1
NR'R
Conversion
100
HNR'R
Heptanamide
95
95
2
3
100
100
99
84
94
84
4b
100
26
84
32
95
26
5
6
100
62
84
63
44
84
58
45
7b
8b
42
a
Ammonolysis of heptanamides (2 mmol) with H3PO4 (1 mmol) and
ethylene glycol (5 mL). Reaction analyzed by GC with 1,3,5-
b
trimethoxybenzene as the internal standard. Yield determined by 1H
Fig. 2 Effect of Lewis (A) and Brønsted (B) acids on the ammonolysis
of heptanilide (2 mmol) in ethylene glycol (5 mL) with dissolved
ammonia (5 M) and 20 mol% acid catalyst. Black bars ¼ aniline, striped
bars ¼ heptanamide.
NMR spectroscopy with 1,3,5-trimethoxybenzene as the internal
standard.
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concentrations (1–3 M) were tested in the H3PO4-promoted spectroscopy. Results with tertiary anilides were variable (entry
ammonolysis of heptanilide, but the yield of heptanamide was 5 vs. 6). Decreased yields were obtained with secondary or
lower than the yield of aniline under these conditions. 2- tertiary amides derived from alkyl amines rather than aryl
Hydroxyethylheptanoate (1), corresponding to the product of amines (entries 7 and 8).
esterication of heptanilide with ethylene glycol, was identied
The other set of substrates that we examined consisted of
as the major by-product (See Fig. S3†). Consequently, the [NH3] anilides bearing different acyl-type groups, including N-
was maintained between 5–9 M in subsequent studies.
phenyl aliphatic and aromatic amides, carbamates, N,N0-
diphenylurea, phthalimide, and toluene sulfonamide (Table
2). Treatment of each of these substrates under the ammo-
nolysis conditions led to excellent yields of aniline in most
cases. Exceptions were pivalanilide (entry 3), which is prob-
ably less reactive owing to steric effects, and the tosylamide
(entry 9), which was unreactive under the reaction condi-
tions. Ammonolysis of N,N'-diphenylurea and N-phenyl-
phthalimide released aniline in excellent yields (entries 10
and 11).
To our knowledge, the results described above represent the
rst effort to optimize the direct ammonolysis of carboxamides.
The use of ethylene glycol, glycerol or another diol as solvents,
and the use of a Brønsted or Lewis acid signicantly promotes
the reaction. The mechanistic basis for the solvent effect is not
yet fully understood, but the empirical data suggest that solvent
polarity and hydrogen bonding effects are important.
The ethylene glycol/phosphoric acid ammonolysis condi-
tions were tested with a number of other heptanamide
substrates (Table 1). The parent heptanilide substrate afforded
a near-quantitative yield of both products aer 15 h (entry 1),
and a similarly good result was obtained with N-8-quinoli-
nylheptanamide (entry 2). The latter result has potential utility
in C–H functionalization chemistry, in light of the widespread
use of the 8-quinolinyl fragment as a directing group.9 Good
reactivity was also observed with N-(2-bromophenyl)heptana-
mide (entry 3), 3,5-dimethoxyheptanilide (entry 4), as well as the
tertiary amide, 1-(2,3-dihydro-1H-indol-1-yl)-1-heptanamide
(entry 8). No side products were observed by GC or NMR
Table 2 Ammonolytic desprotection of anilide derivativesa
Entry
Anilide
Aniline yield (%)
Entry
7
Anilide
Aniline yield (%)
95
1
2
3
100
95
8
95
29
4
5
94
9
0
100
10
100
6
80
11
91
a
Anilides (2 mmol) with H3PO4 (1 mmol), ethylene glycol (5 mL) and anhydrous ammonia (7–9 M) at 145 ꢀC for 15 h. Aniline yield determined by GC
with 1,3,5-trimethoxybenzene as internal standard.
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Acknowledgements
This work was supported by the NSF (CHE-0404704 and CHE-
1307365).
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