carbocationic center. This increased reactivity may be due
to electrostatic effects or inductive effects. In the case of
H2SO4, it is not sufficiently acidic to cleanly ionize the amino
alcohols to the dications and complex product mixtures result.
To characterize the intermediates generated from the amino
alcohols, compounds 9, 10, 26, and 27 were dissolved in
either CF3CO2H or FSO3H-SbF5 and studied by 13C NMR.
Compound 9 ionizes in CF3CO2H to the ammonium cation
31 (Table 2), which shows eight signals for the diastereotopic
phenyl groups. When compound 9 is dissolved in FSO3H-
SbF5 (1:1) and SO2ClF at -60 °C, the dication structure (28)
is observed in the 13C spectrum. The benzylic signal in 31
(77.4 ppm) disappears, and the new carbocationic resonance
appears at 210 ppm, which is comparable to those of other
diphenylmethyl cations.8 Moreover, ionization to the dication
leads to the collapse of the eight aryl signals to four signals.
Compound 10 shows spectral data similar to those of 9: the
Table 2. 13C NMR Data for Cationic Species Arising from
Protonation of Amino Alcohols
monocationic derivative (32) shows eight diastereotopic 13
C
signals for the phenyl groups, while the dicationic derivative
(33) shows the expected four 13C signals. Interestingly, the
13C resonance at 141.6 ppm shows significant broadening
at -50 to -80 °C. This suggests some type of restricted
rotation of the phenyl groups.
When synephrine 26 is ionized in FSO3H-SbF5, the 13C
spectrum shows signals for all nine carbons. This suggests
the formation of a dicationic structure having the positive
charge delocalized into the aryl ring and the p-hydroxy group
(35c). The monocationic derivative (34) shows the expected
number of 13C signals (seven) for that involving a p-
hydroxyphenyl ring. Epinephrine (27) is ionized in CF3CO2H,
and the 13C NMR is consistent with the monocationic
structure 36. The methine carbon appears at 74.9 ppm, and
there are six aryl carbon signals. Upon ionization in FSO3H-
SbF5, the methine signal disappears and 13 downfield signals
appear from 118.2 to 180.4 ppm. These results suggest that
epinephrine also ionizes to a dicationic intermediate (37).
In the case of 27, the 3,4-substitution pattern on the aryl
ring leads to the formation of a mixture of two stereoisomers
of the dication 37.
Several different resonance forms can represent dications
35 and 37. For the synephrine dication, there is the benzylic
cation 35a, the ring-delocalized structures 35b (and the
related 1,5-dication) and 35c, and the quinone methide
structure 35d (Figure 1). The NMR results indicate little or
no rotation of the aryl group and rule against a major
contribution from 35a; this structure is probably disfavored
due to electrostatic effects involving the two charge centers.
Theoretical studies have shown that benzylic cations tend
to delocalize to a greater extent when substituted by adjacent
electron-withdrawing groups or cationic charge centers.9 We
propose that the synephrine dication is a structure which is
best represented by 35b-d. Ab initio calculations were
carried out on the synephrine dication, and the carbon-
(9) Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1989, 111, 34.
(10) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, 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.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, reVision A.9; Gaussian,
Inc.: Pittsburgh, PA, 1998. (b) Geometry optimization was done at the
B3LYP/6-311G level; tables of bond lengths and angles appear in the
Supporting Information.
(6) (a) Klosa, J. J. Prakt. Chem. 1966, 34(5-6), 335. (b) Klosa, J.
Naturwissenschaften 1966, 53(17), 433. (c) Excess AlCl3 itself can produce
superacid-like conditions, and the HCl-AlCl3 system is also a well-known
superacid system, see: Olah, G. A.; Prakash, G. K. S.; Sommer, J. In
Superacids; Wiley: New York, 1985; pp 51-52.
(7) Although no other superacids were used in our synthetic studies, less
expensive superacid systems such as HF-BF3 would be expected to give
comparable results. However, TfOH does not possess the most serious
hazards of the HF-based acid systems. A procedure has been reported for
the quantitative recycling of TfOH: Booth, B. L.; El-Fekky, T. A. J. Chem.
Soc., Perkin Trans. I 1979, 2441.
(8) Dao, L. H.; Maleki, M.; Hopkinson, A. C.; Lee-Ruff, E. J. Am. Chem.
Soc. 1986, 108, 5237.
Org. Lett., Vol. 3, No. 17, 2001
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