Superacid promoted reactions of N-acyliminium salts and evidence for the involvement of superelectrophiles

Article abstract of DOI:10.1039/b708760h

Experimental and theoretical studies suggest the involvement of dicationic, superelectrophilic N-acyliminium ions in conversions catalyzed by superacids. The Royal Society of Chemistry.

Full text of DOI:10.1039/b708760h

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Superacid promoted reactions of N-acyliminium salts and evidence for
the involvement of superelectrophiles{{
Yiliang Zhang, Daniel J. DeSchepper, Thomas M. Gilbert, Kiran Kumar S. Sai and Douglas A. Klumpp*
Received (in Cambridge, UK) 11th June 2007, Accepted 26th July 2007
First published as an Advance Article on the web 23rd August 2007
DOI: 10.1039/b708760h
Experimental and theoretical studies suggest the involvement of
dicationic, superelectrophilic N-acyliminium ions in conversions
catalyzed by superacids.
Over the years, it has been observed that a variety of cationic
electrophiles exhibit significantly enhanced reactivities in super-
acids. This led to a proposal by Olah and coworkers that
electrophiles like the nitronium cation (NO2+) possessing non-
bonded electron pairs are capable of interacting with strongly acidic
media, producing in the limiting case dicationic species
(i.e., HNO22+).1 Due to their ability to react with very weak
nucleophiles, Olah referred to these species as superelectrophiles.
Superelectrophiles have since been proposed in many synthetically
useful reactions, they have been directly observed in NMR and
mass spectral studies, and one example has even been proposed in
a biochemical transformation.2
Scheme 1 Results from the reactions of 2 with varied acids.
The acid-catalyzed reactions of N-acyliminium salts are well
known and have great value in synthetic methodologies.3 Many
of these transformations involve generating the cationic
N-acyliminium ions in excess strong acid. Although these are the
types of conditions that could suggest the involvement of
superelectrophiles, there has been almost no work done to explore
the possibility that superelectrophiles may be involved in this class
of reactions. Perhaps the most closely related work was our recent
study of the aza-Nazarov reaction and Olah’s a-imido-methylation
of deactivated arenes by N-hydroxymethylphthalimide in super-
acid.4 In the following manuscript, we present experimental
evidence for the involvement of protosolovated N-acyliminium
ions in superacid-catalyzed reactions. We also report results from
spectroscopic and computational studies related to these super-
electrophilic species.
generation of the protosolvated species. Similarly, increasing
quantities of superacid tends to increase the bulk acidity of the
reaction media.6
One characteristic of superelectrophiles is their ability to react
with weak nucleophiles, such as deactivated arenes and saturated
hydrocarbons.2 Only a few types of N-acyliminium ions have been
shown to react with deactivated arenes like o-, m- or p-dichloro-
benzene and these reactions have likewise required excess acid to
effect the transformations.7 As part of our studies, the acid-
catalyzed reactions of the pyrrolidinone derivative (5) were
examined (eqn (1)).§
In order to evaluate the effects of acidity on a conversion
involving N-acyliminium salts, the reaction of acetylated
benzilidine aniline with benzene was studied (Scheme 1).5 Two
notable observations were seen: the yield of product
4
increases markedly with the acidity and quantity of the acid
catalyst. These results are consistent with protosolvation of
the N-acyliminium ion to give an electrophile with increasing
dipositive character (i.e. 3). Since the N-acyliminium ion
itself is a weak base, increasing acid strength should favor
ð1Þ
In the reaction with p-dichlorobenzene and CF3SO3H, pyrrolidi-
none 5 is arylated in reasonably good yield (60%) to give product
8. Similar results are obtained from the superacid-promoted
reaction of o-dichlorobenzene and compound 5. It is proposed that
the N-acyliminium ion (6) is formed" and protonation of this
species leads to the superelectrophile (7a or 7b). When the
substantially weaker acid CF3CO2H is used in the same
transformations, there are no reactions with the deactivated arene
nucleophile (eqn (2)).
Department of Chemistry and Biochemistry, Northern Illinois
University, DeKalb, Illinois 60115, USA. E-mail: dklumpp@niu.edu;
Fax: 815-753-4802; Tel: 815-753-1959
{ Electronic supplementary information (ESI) available: Experimental
methods, spectral data of new compounds, computational methods and
results, and NMR spectra. See DOI: 10.1039/b708760h
{ Dedicated to Professor George A. Olah on the occasion of his 80th
birthday.
4032 | Chem. Commun., 2007, 4032–4034
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dication 7b were calculated to be minima on the potential energy
surface with the trans-protonated structure found to be
3.1 kcal mol21 more stable than the cis-protonated structure
(MP2/6-311+G(d) level). For the calculated gas-phase reactions,
the conversion of the monocationic electrophile 6 to the s-complex
10 is found to be somewhat endothermic. At the MP2/6-311+G(d)
level, no minimum could found for the s-complex and during
optimization, complex 10 dissociates to benzene and 6. If the ring–
ring bond is fixed however, the potential energy of the resulting
structure can be estimated. Protonation of 6 gives the super-
electrophile 7b, which is found to react with benzene in an initial
reaction step that is significantly exothermic. At both levels of
theory, structure 11 is found at a minimum on the potential energy
surface. In accord with earlier theoretical studies on super-
electrophiles,2 reactions that disperse the positive charge tend to
be energetically favorable. In the case of 7b, formation of the
s-complex (11) leads to wide separation of the two positive
charges. Similarly, the protosolvated species (7a) is expected to
possess favorable energetics in its reaction with benzene.
ð2Þ
However when the activated arene and stronger nucleophile,
p-dimethoxybenzene, is reacted with compound 5 in CF3CO2H,
the arylated product (9) is formed. This indicates that the weaker
acid is capable of producing the N-acyliminium ion (6), but
without further protolytic activation, the N-acyliminium ion is not
sufficiently electrophilic to attack p-dichlorobenzene. Reaction in
superacid leads to the formation of dication 7a or 7b and
subsequent chemistry with the deactivated arene. When the
pyrrolidinone (5) is reacted with benzene and CF3SO3H, the
phenylated product (1-methyl-5-phenylpyrrolidin-2-one) is
obtained in 86% yield. An earlier report describes a similar
reaction between the N-acyliminium ion 6 (formed by decarbony-
lation of pyroglutamic acids) and benzene in the weaker acid
system, P2O5–CH3SO3H, however the yield is only 27%.8 This
suggests a greater degree of N-acyliminium ion protosolvation in
the superacidic CF3SO3H.
Using stable ion conditions pioneered by Olah and co-workers,
varied onium cations and electrophiles have been directly observed
over the years by low temperature NMR spectroscopy.10 The
pyrrolidinone derivative (5) was studied by stable ion conditions
using low temperature 13C NMR and the results are consistent
with the formation of the protosolvated species in superacidic
media. With solvation in CF3CO2H, compound 5 gives a complex
NMR spectrum with roughly twenty 13C NMR peaks (Table 1).
This complex spectrum is likely the result of an equilibrium
mixture containing the starting pyrrolidinone 5, the N-acyliminium
ion 6, and other species. In superacidic FSO3H, a clean spectrum is
generated from the pyrrolidinone 5, and the data suggests
complete conversion to the N-acyliminium ion 6. Based on the
calculated spectrum for 6, the peaks at d 178.4 and 198.6 are
assigned to the carbonyl and iminium carbons, respectively. The
observed chemical shift values from FSO3H are in good agreement
with both the calculated spectrum for 6 and the reported 13C
In order to further explore this chemistry, theoretical calcula-
tions were done to estimate the effects of protosolvation on the
energetics of the N-acyliminium ions (6 and 7b) and its reaction
with benzene. Calculations were done at the HF/6-311+G(d) and
MP2/6-311+G(d) levels of theory (Fig. 1).9 Two stereoisomers of
1
NMR spectrum of an N-acyliminium ion.11 Analysis of the H
NMR also suggests clean formation of the N-acyliminium ion 6,
with the iminium proton appearing down-field at d 8.92. When the
pyrrolidinone derivative 5 is reacted with FSO3H–SbF5 at 240 uC,
1
two sets of NMR peaks are observed in the H and 13C spectra
Fig. 1 Calculations related to the phenylation of 6 and 7b and the
estimated DHreactions for the respective s-complexes 10 and 11.
(formed in roughly a 6 : 1 ratio). The major product gives 13C
Table 1 13C and 1H NMR spectral data for pyrrolidinone 5 in acidic media and the calculated 13C NMR data (MP2/6-311+G(d) level) for 6 and
7b (trans stereoisomer)
Acid (acid strength)
Temp./uC
25
NMR signals
CF3CO2H (H0 22.7)
FSO3H–SO2ClF (H0 215)
13C: Complex spectrum (ca. 20 peaks)
240
13C, d: 24.7, 30.7, 33.9, 178.4, 198.6
1H, d: 2.28 (2H), 2.75 (2H), 2.91 (3H), 8.92 (1H)
FSO3H–SbF5–SO2ClF (H0 225)
240
13C, d: 25.4, 31.5, 34.2, 181.9, 201.3
Major product
Minor product
1H, d: 2.26 (2H), 2.70 (2H), 2.82 (3H), 8.87 (1H)
13C, d: 31.3, 35.4, 36.4, 200.6, 214.3
1H, d: 3.01 (2H), 3.10 (3H), 3.19 (2H), 9.42 (1H)
Calculated NMR signals (6):
Calculated NMR signals (7b):
13C, d: 23.0, 29.7, 37.5, 179.2, 207.7
13C, d: 30.7, 37.1, 44.1, 226.5, 244.4
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(CDCl3, 125 MHz): d 26.4, 28.6, 29.2, 61.0, 126.4, 129.0, 131.0, 131.4,
resonances at: d 25.4, 31.5, 34.2, 181.9, 201.3. These peaks are
assigned to the N-acyliminium ion 6. The smaller set of peaks
appear at: d 31.3, 35.4, 36.4, 200.6, 214.3, and based on the
deshielding of the carbons, these peaks can be assigned to the
protosolvated species 7a. Likewise, all of the 1H NMR peaks are
significantly deshielded (note the iminium proton at d 9.42),
suggesting the protosolvated structure 7a. The new carboxonium
133.6, 140.1, 175.7. Low resolution mass spectrum (EI): m/z: 243 (M+), 188,
115, 98. High resolution mass spectrum for C11H11ONCl2, calc: 243.0218,
found: 243.0213. Anal. Calc. for C11H11ONCl2: C, 54.12; H, 4.54; N, 5.74.
Found: C, 54.23; H, 4.58; N, 5.72%.
" Observation of N-acyliminium ion 6: Triple-distilled (Aldrich) FSO3H
(0.5 mL) is added to a dried, Ar-filled test tube (or flask) and cooled to
278 uC. To the FSO3H is added SO2ClF16 (0.5 mL) and the solution is
mixed. 1-Methyl-5-hydroxypyrrolidin-2-one12 (5, 20–30 mg) is then added
to the acidic solution. With vigorous stirring, compound 5 dissolves and the
resulting solution is transferred to a dried, cold NMR tube (previously
cooled to 278 uC). A coaxial insert containing acetone-d6 is then inserted
into the NMR tube and the NMR spectrum is taken with the NMR probe
cooled to 240 uC.
1
proton of 7a is not seen in the H NMR, possibly due to rapid
exchange or being obscured by the large 1H signal from the acidic
media. The carboxonium carbon of superelectrophile 7a is
observed at d 200.6 and this is similar to the carboxonium 13C
resonances of other dicationic systems. For example, the 13C
NMR spectra of diprotonated 2-pyridinecarbaldehyde and 2,3-
butanedione monooxime were recently reported and the respective
carboxonium carbons are found at d 203.6 and 219.2.12
1 G. A. Olah, A. Germain, H. C. Lin and D. Forsyth, J. Am. Chem. Soc.,
1975, 97, 2928.
2 G. A. Olah and D. A. Klumpp, Superelectrophiles and their Chemistry,
Wiley, New York, 2007; G. A. Olah and D. A. Klumpp, Acc. Chem.
Res., 2004, 37, 211; G. A. Olah, Angew. Chem., Int. Ed. Engl., 1993, 32,
767.
3 B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi and
C. A. Maryanoff, Chem. Rev., 2004, 104, 1431; W. N. Speckamp and
M. J. Moolenaar, Tetrahedron, 2000, 56, 3817.
4 D. A. Klumpp, Y. Zhang, M. J. O’Connor, P. M. Esteves and
L. S. de Almeida, Org. Lett., 2007, 9, 3085; G. A. Olah, Q. Wang,
G. Sandford, A. B. Oxyzoglou and G. K. S. Prakash, Synthesis, 1993,
1077 see also ref. 5.
5 Y. Zhang, P. J. Kindelin, D. DeSchepper, C. Zheng and D. A. Klumpp,
Synthesis, 2006, 1775. A modest improvement in the yield of product 4
has been achieved in the present study, compared to our earlier study
(ref. 5). This is attributed to the use of CH2Cl2 as a solvent for the
acetylation of imine.
6 G. A. Olah, G. K. S. Prakash and J. Sommer, in Superacids, Wiley,
New York, 1985.
7 R. Schmidt and E. Schlipf, Chem. Ber., 1970, 103, 3783.
8 B. Rigo, D. Fasseur, N. Cherepy and D. Couturier, Tetrahedron Lett.,
1989, 30, 7057.
9 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery, Jr.,
R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam,
A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo,
S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui,
K. Morokuma, A. D. Malick, K. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G. Baboul, B. B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts,
R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
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E. S. Replogle and J. A. Pople, Gaussian 98, Revision A.11.4, Gaussian,
Inc., Pittsburgh PA, 1998.
The calculated gas-phase NMR spectrum of the fully proto-
nated dication (7b) shows carboxonium and iminium carbons that
are significantly deshielded from the experimentally observed
signals in FSO3H–SbF5 solution.13 This suggests that the superacid
produces the protosolvated species 7a from the pyrrolidinone 5,
rather than the fully formed dicationic superelectrophile 7b.
In summary, we have found evidence for the involvement of
superelectrophilic intermediates in the superacid-promoted reac-
tions of N-acyliminium ions. In the condensed phase, the acid-
catalyzed reactions of N-acyliminium ions show a significant
dependence on acid strength and quantity. Electrophilic strength
increases with acidity. The pyrrolidinone 5 is also shown to be
capable of reacting with deactivated arenes in superacid.
Moreover, both the N-acyliminium ion 6 and its protosolvated
species (7a) can be directly observed by low temperature 13C
NMR. Theoretical calculations also show that formation of the
superelectrophile 7b leads to more favorable energetics in the
reaction with benzene.
Acknowledgement is made to the NIH-NIGMS (GM071368-
01) and the Petroleum Research Fund administered by the
American Chemical Society (PRF# 44697-AC1) for their financial
support.
10 G. A. Olah, K. K. Laali, Q. Wang and G. K. S. Prakash, Onium Ions,
Wiley, New York, 1998.
11 Y. Yamamoto, T. Nakada and H. Nemoto, J. Am. Chem. Soc., 1992,
114, 121.
12 D. A. Klumpp, Y. Zhang, P. J. Kindelin and S. Lau, Tetrahedron, 2006,
62, 5915; T. Ohwada, T. Yamazaki, T. Suzuki, S. Saito and K. Shudo,
J. Am. Chem. Soc., 1996, 118, 6224.
13 Calculated 13C NMR GIAO results were also obtained for the less
stable cis stereoisomer of 7b, d: 31.5, 37.0, 39.6, 222.9, 247.8.
14 Available commercially or may be prepared: J. C. Hubert, J. B. P. A.
Wijnberg and W. N. Speckamp, Tetrahedron, 1975, 31, 1437.
15 CF3SO3H may be quantitatively recycled, see: B. L. Booth and T. A. El-
Fekky, J. Chem. Soc., Perkin Trans. 1, 1979, 2441.
Notes and references
§ Reaction of pyrrolidinone 5: 1-Methyl-5-hydroxypyrrolidin-2-one14 (5,
0.9 mmol) and p-dichlorobenzene (0.5 g, 3.4 mmol) are added to 3 mL of
freshly distilled CF3SO3H15 and the mixture is heated to 80 uC. After
stirring for 2 h, the mixture is poured over about 10 g of ice and the
resulting solution is extracted with CHCl3. The organic phase is washed
with water, then brine, and dried with anhydrous Na2SO4. Isolation of the
product by column chromatography (hexanes–ether) yields 0.13 g of 5-(2,5-
dichlorophenyl)-1-methylpyrrolin-2-one (8, 0.54 mmol, 60%) as colorless
crystals, mp 59–61 uC (diethyl ether). 1H NMR (CDCl3, 500 MHz): d 1.73–
1.79 (m, 1H), 2.33–2.56 (m, 3H), 2.70 (s, 3H), 4.89–4.93 (m, 1H), 6.98–7.02
(m, 1H), 7.14-7.19 (m, 1H), 7.28 (dd, 1H, J = 1.0, 8.5 Hz). 13C NMR
16 Available commercially or may be prepared: V. P. Reddy, D. R. Bellew
and G. K. S. Prakash, J. Fluorine Chem., 1992, 56, 195.
4034 | Chem. Commun., 2007, 4032–4034
This journal is ß The Royal Society of Chemistry 2007