Superacidic activation of quinoline and isoquinoline; their reactions with cyclohexane and benzene

Article abstract of DOI:10.1021/jo070875x

(Chemical Equation Presented) Quinoline (1) and isoquinoline (2), upon activation by strong acids, lead to intermediate N,C-diprotonated dications, which are involved in reactions with weak nucleophiles. Thus, 1 and 2 undergo selective ionic hydrogenation with cyclohexane in CF₃SO ₃H-SbF₅, HBr-AlBr₃-CH₂Br ₂, or HCl-AlCl₃-CH₂Cl₂ acid systems to give their 5,6,7,8-tetrahydro derivatives. They also readily condense with benzene in the presence of HBr-AlBr₃ or HCl-AlCl₃ to provide 5,6,7,8-tetrahydro-5,7-diphenylquinoline (10) and 5,6,7,8-tetrahydro-6, 8-diphenylisoquinoline (12), respectively.

Full text of DOI:10.1021/jo070875x

3
Superacidic Activation of Quinoline and
halides. The key intermediates of these reactions were recog-
4
nized to be superelectrophilic N,C-diprotonated dications of
Isoquinoline; Their Reactions with Cyclohexane
1
the heterocycles. Moreover, many such long-lived dications 3-8
have been generated in the CF3SO3H-SbF5 acid system.3
Obviously, the hydroxyl group plays an important role in
stabilizing these dicationic intermediates.
and Benzene
,
†,‡
†
Konstantin Yu. Koltunov,* G. K. Surya Prakash,
†
†
Golam Rasul, and George A. Olah
Loker Hydrocarbon Research Institute and Department of
Chemistry, UniVersity of Southern California, UniVersity Park,
Los Angeles, California 90089-1661, BoreskoV Institute of
Catalysis, Pr. Akademika LaVrentieVa, 5, NoVosibirsk, 630090,
Russia, and NoVosibirsk State UniVersity, PirogoVa, 2,
NoVosibirsk 630090, Russia
koltunoV@catalysis.ru
ReceiVed May 12, 2007
Taking into account practical importance of quinoline and
isoquinoline scaffolds in organic chemistry, the objective of the
present work is to extend our investigation to readily available
parent compounds 1 and 2 and involve them in similar model
reactions with cyclohexane and benzene in strong acids. The
main aim of the work was also to generate nonstabilized N,C-
diprotonated dications derived from 1 and 2 under the reaction
conditions.
NMR Study of Protonation of 1 and 2 and a Theoretical
Study of Probable N,C-Diprotonated Dications. Initially, we
examined the protonation of 1 and 2 using such superacidic
system as CF3SO3H-SbF5 at 25 °C and more acidic HSO3F-
SbF5(1:1)-SO2ClF and HF-SbF5(5:1)-SO2ClF systems at -60 °C
by means of H and C NMR spectroscopy. Unfortunately,
under these conditions, only the N-protonated monocations of
the precursors were formed as long-lived species, indicating,
as expected, the difficulty of subsequent C-protonation. How-
ever, N,C-diprotonated species may be involved in a relatively
small equilibrium.
Quinoline (1) and isoquinoline (2), upon activation by strong
acids, lead to intermediate N,C-diprotonated dications, which
are involved in reactions with weak nucleophiles. Thus, 1
and 2 undergo selective ionic hydrogenation with cyclohex-
ane in CF
AlCl -CH
derivatives. They also readily condense with benzene in the
presence of HBr-AlBr or HCl-AlCl to provide 5,6,7,8-
tetrahydro-5,7-diphenylquinoline (10) and 5,6,7,8-tetrahydro-
3
SO
3
H-SbF
5
, HBr-AlBr
3
-CH
2
Br
2
, or HCl-
1
13
3
2
Cl
2
acid systems to give their 5,6,7,8-tetrahydro
3
3
6,8-diphenylisoquinoline (12), respectively.
The second protonation can lead to a number of isomeric
N,C-diprotonated dications of structures 1a-e and 2a-e,
respectively, as the most plausible (Table 1). In order to estimate
the relative stabilities, electrophilicities, and positions of elec-
trophilic centers of the preferred dications, we have calculated
their relative energies, the energies of lowest unoccupied
molecular orbital (ꢀLUMO), the squares of the coefficients of
The facile N,C-diprotonation of quinoline (1) and isoquinoline
2) in strong acid solution was surmised based on the kinetic
(
study of their H/D exchange reaction with deuteriosulfuric acid
2
at high temperatures. The deuteriation occurs at positions 8 >
5
, 6 > 7 > 3 and 5 > 8 > 7 of 1 and 2, respectively, indicating
facile protonation of the carbocyclic ring of the N-protonated
2
carbon atoms at LUMO of electrophilic centers (c• ) and the
atomic charges of electrophilic centers (q•) localized at carbon
2
heterocycles. Surprisingly, the literature appears to contain no
reports on the use of this remarkable property of 1 and 2 as a
method of electrophilic activation, which could be of interest
from a synthetic point of view. Indeed, we recently have shown
that a variety of isomeric hydroxy(iso)quinolines condense with
benzene and undergo ionic hydrogenation with cyclohexane in
protonic superacids or in the presence of excess of aluminum
atoms and pendent hydrogen atoms. Calculations were carried
5
out with the Gaussian 98 program system. The geometry
6
optimization was performed using the DFT method at the
7
8
B3LYP /6-31G* level. Vibrational frequency at the B3LYP/
(3) (a) Koltunov, K. Yu.; Prakash, G. K. S.; Rasul, G.; Olah, G. A.
Heterocycles 2004, 62, 757. (b) Koltunov, K. Yu.; Prakash, G. K. S.; Rasul,
G.; Olah, G. A. J. Org. Chem. 2002, 67, 4330. (c) Koltunov, K. Yu.;
Prakash, G. K. S.; Rasul, G.; Olah, G. A. J. Org. Chem. 2002, 67, 8943.
(d) Koltunov, K. Yu.; Repinskaya, I. B. Russ. J. Org. Chem. 2002, 38,
437.
(4) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (b)
Nenajdenko, V. G.; Shevchenko, N. E.; Balenkova, E. S.; Alabugin, I. V.
Chem. ReV. 2003, 103, 229. (c) Olah, G. A.; Klumpp, D. A. Acc. Chem.
Res. 2004, 37, 211.
*
To whom correspondence should be addressed.
Loker Hydrocarbon Research Institute.
Boreskov Institute of Catalysis and Novosibirsk State University.
†
‡
(
1) Chemistry in Superacids. Part 68. For part 67, see: Koltunov, K.
Yu.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. Eur. J. Org. Chem. 2006,
861.
2) Bressel, U.; Katritzky, A. R.; Lea, J. R. J. Chem. Soc. B 1971, 4,
and references cited therein.
4
(
10.1021/jo070875x CCC: $37.00 © 2007 American Chemical Society
7
394
J. Org. Chem. 2007, 72, 7394-7397
Published on Web 08/18/2007

TABLE 1. Energies of the LUMO (ELUMO), the Square of the
All dications 1a-e and 2a-e according to the calculated
values of the ꢀLUMOs (∼-13 eV) are stronger electrophiles than
2
a
Coefficients on Carbon Atoms at the LUMO (ci ), NBO Charges on
a
CH Groups (qi) and Total Energies (-au), ZPE, and Relative
3
their hydroxyl-substituted derivatives (ꢀLUMO ∼ -12.5 eV) and
Energies of Dications 1a-e and 2a-e Calculated by the DFT
therefore appear to be capable of reacting with benzene and
cyclohexane.
Method
The computed relative energies show the order of favorable
formation of the dications as follows, 1d > 1a > 1b > 1c >
1
e and 2a > 2d > 2c > 2b > 2e, corresponding to second
protonation of 1 and 2 in positions 8, 5, 6, 7, 3 and 5, 8, 7, 6,
, respectively. This is in accordance with the previous
4
2
deuteriation studies of 1 and 2 in D2SO4.
Dication 2a is more stable than dication 1d, indicating that,
in general, isoquinoline 2 is more easily activated (by N,C-
diprotonation) than quinoline 1. The significant values of both
2
5
of c• and q• predict electrophilic reaction centers to be C or
7
6
8
C and C or C for dications 1d and 2a, respectively. Similarly,
one can easily predict electrophilic centers for other isomeric
dications.
Reactions with Cyclohexane and Benzene. Compounds 1
and 2 did not react with benzene and cyclohexane in trifluo-
romethanesulfonic acid (CF3SO3H, Ho ) -14.1) or in the
presence of excess of aluminum halides at 20-100 °C.
However, successful results were achieved in strong conjugate
protic acid systems such as CF3SO3H-SbF5 (Ho ∼ -18), HBr-
AlBr3 (Ho ∼ -17.5) or HCl-AlCl3.
Quinoline 1, for example, slowly reacts with cyclohexane in
CF3SO3H-SbF5 system at room temperature and in HBr-
AlBr3-CH2Br2 system at 70 °C over period of 24 and 150 h,
respectively, to give 5,6,7,8-tetrahydroquinoline (9) as a single
product (Scheme 1). According to the Scheme 1, the probable
mechanism of this reaction includes generation of the dication
1
d′ (as the major intermediate) followed by its selective ionic
hydrogenation with cyclohexane.
More readily, over period 10 h at 25 °C, compound 1 reacts
with benzene and with HBr-AlBr3 to give 5,6,7,8-tetrahydro-
5
,7-diphenylquinoline (10) in 75% isolated yield (Scheme 1).
The same reaction also takes place under the influence of HCl-
AlCl3, but more slowlysthe conversion of 1 is about 40% over
a period of 100 h at 25 °C. The preferred mechanism of the
reaction, involving the intermediacy of the dication 1d′ and its
subsequent condensation with benzene, is shown in Scheme 1.
Compound 2, which according to theory (vide supra) is more
easily activated than 1, appears to be more reactive. Reaction
of 2 with cyclohexane occurred in the CF3SO3H-SbF5 system
(5) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, R. E.; Kudin, K.
N.; Strain, M. C.; Farcas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelly, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A.D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J.
V.; Stefanov, B. B.; Liu, G., Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkarra, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Jonson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C. M.; Head-
Gordon, M.; Pople, J. A. Gaussian 98 (Revision A.5); Gaussian, Inc.,
Pittsburgh, PA 1998.
a
These parameters are given for atoms belonging to C-protonated ring
2
and with the most significant values of ci at LUMO and qi.
6
-31G*//B3LYP/6-31G* level was used to characterize station-
ary point as minimum (number of imaginary frequency (NIMAG)
0) and to evaluate zero point vibrational energies (ZPE),
which were scaled by a factor of 0.98. Relative energies were
calculated at the B3LYP/6-31G*//B3LYP/6-31G*+ZPE level.
The values of q• were obtained using natural bond orbital
(
6) Ziegler, T. Chem. ReV. 1991, 91, 651.
(7) Becke’s three-parameter hybrid method using the LYP correlation
)
functional: (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. ReV. B. 1988, 37, 785. (c) Stephens, P. J.;
Devlin, F. J.; Chabalovski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98,
1
1623.
(8) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
9
analysis (NBO) method. Results of calculations are summarized
in the Table 1.
Molecular Orbital Theory; Wiley-Interscience: New York, 1986.
(9) Reed, A. E.; Curtiss, L. A.; Wienhold, F. Chem. ReV. 1988, 88, 899.
J. Org. Chem, Vol. 72, No. 19, 2007 7395

SCHEME 1
SCHEME 2
FIGURE 1. Molecular structure of cis-10 (A) and trans-12 (B)
hydrochlorides.
experimental results can be successfully explained by the
involvement of N,C-diprotonated dications of 1 and 2 as key
superelectrophilic intermediates. This also conforms to results
of theoretical calculations on these dications. In general, the
observed reactivity of such nonactivated heterocycles as 1 and
at room temperature to give 5,6,7,8-tetrahydroisoquinoline (11)
in 94% yield over a period of 2 h (Scheme 2). The reaction
also took place slowly (period of half of the reaction g250 h)
in HBr-AlBr3-CH2Br2 and HCl-AlCl3-CH2Cl2 acid systems
at room temperature and in the presence of HCl-AlCl3 at
elevated temperatures (80-110 °C, in a pressure tube). Reacton
of 2 with benzene occurred in the presence of HBr-AlBr3 and
HCl-AlCl3 at room temperature to provide 5,6,7,8-tetrahydro-
2
seems promising for practical applications. We suggest that
analogous approach can be followed to perform similar modi-
fications of a large variety of aromatic heterocycles.
6
,8-diphenylisoquinoline (12) in good yield (∼90%) over
Experimental Section
periods of 1 and 72 h, respectively (Scheme 2). The mechanism
of the reactions of compound 2 with cyclohexane and benzene,
which include the intermediacy of dication 2a (or analogous
protonated complexes with aluminum halides), is considered
similar to that described in Scheme 1.
5
,6,7,8-Tetrahydroquinoline (9). Method a. To a solution of
(0.03 g, 0.23 mmol) in CF SO H (0.7 g, 4.7 mmol) was added
SbF (0.66 g, 3 mmol) at room temperature. After subsequent
1
3
3
5
addition of cyclohexane (0.3 mL), the reaction mixture was stirred
at 25 °C for 24 h. After the reaction, the reaction mixture was
quenched with several grams of ice. The aqueous layer was washed
with ether and then made basic with aqueous NaOH and extracted
It should be stressed that the experimentally found regiose-
lectivity of the reactions both of 1 and 2 with benzene
corresponds to the involvement of the most stable (easily
produced) dications 1d and 2a, respectively. This is not
surprising, taking into account difficulty of the second proto-
nation, which is regarded as a limiting step.
4
with ether. The organic phase was dried over anhydrous MgSO .
Careful removal of the solvent under reduced pressure provided
the mixture of product 9 and precursor 1 (0.029 g, the ratio 1:1).
The mixture was separated by silica gel column chromatography
with acetone-benzene as eluent to give product 9 (0.013 g, 42%)
It should be also noted that both diphenyl-derivatives 10 and
1
2 are obtained mainly in the form of thermodynamically
1
13
as a colorless liquid. NMR H and C data of 9 are comparable to
preferred cis-isomers. This was confirmed by X-ray crystal-
lographic analyses performed on the hydrochloric acid salts of
the predominant cis-10 and minor trans-12 isomers (Figure 1;
see the Supporting Information for details).
those previously reported.3b
3 2 2
Method b. To a solution of AlBr (2 g, 7.5 mmol) in CH Br (2
mL) was added 1 (0.3 g, 2.3 mmol) and cyclohexane (2 mL). The
resulting mixture was saturated with gaseous HBr (0.2 g, 2.5 mmol)
and stirred at 70 °C in a 15 mL pressure tube for 150 h followed
by workup described above to provide 0.28 g of the mixture of
product 9 and precursor 1 (in a 1:1 ratio).
Conclusions
In summary, compounds 1 and 2 undergo selective ionic
hydrogenation with cyclohexane and condense with benzene
in strong acidic media to give respective products 9-12. All
5,6,7,8-Tetrahydro-5,7-diphenylquinoline (10). To a solution
of AlBr (4 g, 15 mmol) in benzene (15 mL) was added 1 (0.6 g,
3
7
396 J. Org. Chem., Vol. 72, No. 19, 2007

4
.7 mmol). The resulting solution was saturated with gaseous HBr10
3 2 2
Method b. To a solution of AlBr (2 g, 7.5 mmol) in CH Br (2
(
∼0.5 g, 6 mmol) and stirred at 25 °C for 10 h, then poured over
mL) was added 2 (0.3 g, 2.3 mmol) and cyclohexane (2 mL). The
resulting mixture was saturated with gaseous HBr (0.2 g, 2.5 mmol)
and stirred at 25 °C for 250 h followed by usual workup to give
0.29 g as a mixture of product 11 and precursor 2 (in a 1:1 ratio).
ice. The resulting mixture was made basic with aqueous NaOH
and extracted with ether. The organic phase was dried over
anhydrous MgSO
product,11 which was purified by silica gel column chromatography
with CH Cl to give colorless syrup-like product 10 (1 g, 75%) as
a mixture of cis/trans isomers (in a 3:1 ratio, respectively): HRMS
19N calcd 285.1518, found 285.1509. Recrystallization from
O-ethanol (1:2) (provided with cooling at -20 °C) gave cis-10
4
and concentrated in vacuo to obtain the crude
5,6,7,8-Tetrahydro-6,8-diphenylisoquinoline (12). Method a.
2
2
To a solution of AlBr (4 g, 15 mmol) in benzene (15 mL) was
3
added 2 (0.6 g, 4.7 mmol). The resulting solution was saturated
C
H
21
H
10
with gaseous HBr (∼0.5 g, 6 mmol) and stirred at 25 °C for 1 h,
2
and after workup and purification described above for product 10
gave colorless syrup-like product 12 (1.21 g, 91%) as a mixture of
1
(
0.57 g, 43%) as white crystals: mp 117-118 °C; H NMR (CDCl
3
)
δ 2.12 (q, J 12 Hz, 1H), 2.37-2.43 (m, 1H), 3.2-3.4 (m, 3H),
4
cis/trans isomers (ratio 2.5:1, respectively): HRMS C21
H19N calcd
.25 (dd, J 12, 5.6 Hz, 1H), 7.01 (dd, J 7.8, 4.5 Hz, 1H), 7.1-7.4
2
85.1518, found 285.1512.
1
3
7
(
m, 11H), 8.41 (d, J 4.5 Hz, 1H); C NMR (CDCl
3
) δ 40.6 (C ),
cis-12:13 1H NMR (CDCl
3
) δ 2.09 (q, J 12.5 Hz, 1H), 2.42 (dd,
6
8
5
3
4
1
1
0.9 (C ), 41.1 (C ), 46.8 (C ), 121.2 (C ), 126.4, 126.5, 126.6,
J 12.5, 6.8 Hz, 1H), 3.1-3.24 (m, 3H), 4.26 (dd, J 12.5, 6.8 Hz,
2
′-6′
10
4
28.5, 128.5, 128.6 (5-and 7-Ph, C
), 134.8 (C ), 137.1 (C ),
13
1
H), 7.0-7.4 (m, 11H), 8.09 (s, 1H), 8.33 (d, J 5.1 Hz, 1H); C
1′
1′
2
9 12
45.1 (7-Ph, C ), 145.3 (5-Ph, C ), 147.2 (C ), 156.9 (C ).
NMR (CDCl
3
) δ 38.1, 40.7, 41.4, 45.7, 123.4, 126.6, 126.6, 126.7,
trans-10:1 H NMR (CDCl
H), 3.1-3.42 (m, 3H), 4.29 (t, J 4.9 Hz, 1H), 7.0-7.2 7.1-7.4
) δ 34.9,
3 1
) δ 2.2-2.3 (m, 1H), 2.35-2.45 (m,
3
127.6, 128.5, 128.6, 128.8, 145, 145.9, 146.4, 146.6, 151.2.
1
(
3
1
trans-12:13 1H NMR (CDCl
) δ 2.2-2.3 (m, 1H), 2.35-2.45 (m,
m, 12H), 8.49 (dd J 4.7, 1.7 Hz, 1H); 13C NMR (CDCl
3
3
1
8
3
1
H), 2.8-3.3 (m, 3H), 4.39 (d, J 5 Hz, 1H), 7.0-7.4 (m, 11H),
8.5, 39.6, 43.4, 121.4, 126.3, 126.3, 126.9, 128.3, 128.5, 128.7,
36, 138.1, 145, 146.1, 147.8, 157.3.
5
.25 (s, 1H), 8.38 (d, J 5.1 Hz, 1H); 13C NMR (CDCl
) δ 34.5,
3
6.8, 38.6, 41.8, 123.6, 126.3, 126.4, 126.8, 127.4, 128.3, 128.5,
28.6, 145.2, 145.8, 146.8, 146.9, 152.
,6,7,8-Tetrahydroisoquinoline (11). Method a. To a solution
of 2 (0.04 g, 0.31 mmol) in CF SO H (1 g, 6.7 mmol) was added
SbF (0.8 g, 3.7 mmol). After subsequent addition of cyclohexane
0.2 mL), the reaction mixture was stirred at 25 °C 2 h followed
3
3
3
Method b. To a stirred suspension of AlCl (5.6 g, 42 mmol) in
5
benzene (15 mL) was added 2 (2 g, 16 mmol). The resulting mixture
was saturated with gaseous HCl and then maintained under stirring
at 25 °C for 72 h. Workup and purification as described above
gave 12 (3.71 g, 84%).
(
by usual workup to give product 11 (0.039 g, 94%) as a colorless
liquid. NMR data of 11 are comparable to those previously
reported.3b
Acknowledgment. Support of this work by the National
Science Foundation and the Loker Hydrocarbon Research
Institute is gratefully acknowledged. We also thank N.V.
Kuratieva and Dr. S.A. Gromilov (Nikolaev Institute of
Inorganic Chemistry, Novosibirsk) for the X-ray analysis.
(
10) Gaseous HBr can be easily obtained by reaction of benzene with
Br2 in the presence of AlBr3 and used without subsequent purification.
Moreover, HBr can be produced in a “one pot reaction” by careful addition
of Br2 to the stirring solution of AlBr3 and 1 (or 2) in benzene at 0 to 5 °C.
(
11) According to NMR and GC-MS data, the crude product contains
1
0 (>75%) along with variety of phenylquinolines, phenyltetrahydroquino-
lines, and unidentified 5,6,7,8-tetrahydrodiphenylquinoline (structural isomer
of 10, <10%). Crystallization of this mixture from aqueous ethanol gives
cis-10.
Supporting Information Available: Cartesian coordinates and
total energies (hartrees) of the optimized geometries of 1a-e and
(
12) The structural assignment was performed by the INADEQUATE
1
13
(13
13
2a-e, H and C NMR spectroscopic data of 10 and 12, and X-ray
crystallographic data (CIF) for cis-10 and trans-12 hydrochloride
salts. This material is available free of charge via the Internet at
http://pubs.acs.org.
C- C correlation) experiment on a 500 MHz NMR spectrometer (see
the Supporting Information).
13) The chemical shifts are taken from the spectrum of a mixture of
(
the cis and trans isomers. The assignment of signals to each of these isomers
was simplified by changing the ratio of the isomers using additional column
chromatography treatments and other methods.
JO070875X
J. Org. Chem, Vol. 72, No. 19, 2007 7397