J . Org. Chem. 1996, 61, 9033-9034
9033
the open ion as the most reasonable precursor to 2.
However, acetolysis of enantiomerically enriched 1-O-
COCF 3 occurs with partial retention of configuration,
which is consistent with the presence of a mixture of the
open and closed ions in acetic acid.4 Whatever its
structure, our results show that in 50/50 (v/v) trifluoro-
ethanol/water a major reaction of 1+ is its cyclization to
give 2. However, there is no large accumulation of 2
because it subsequently undergoes rapid nucleophilic
addition to 1+ that is formed continuously during the
reaction of 1-P F B.
Rela tive Rea ctivities of a Str on gly
Nu cleop h ilic Alk en e a n d Azid e Ion in
Aqu eou s Meth a n ol
J ohn P. Richard,* Shrong-Shi Lin, and
Kathleen B. Williams
Department of Chemistry, University at Buffalo,
SUNY, Buffalo, New York 14260-3000
Received J uly 12, 1996
In the more nucleophilic solvent of 50/50 (v/v) methanol/
water, 3 is formed only as a minor product of the reaction
of 1+. A selectivity of kaz/ks ) 70 000 M-1 for partitioning
of 1+ between reaction with azide ion and solvent was
determined from the yields of the products of the reaction
of 1-P F B (5 × 10-5 M) according to eq 1, where [1-N3]/
[1-OSolv] is the ratio of the yields of the azide ion adduct
and the sum of the yields of the solvent adducts (1-OH
and 1-OMe). In this solvent, the electrophile 1+ is also
trapped by added 2 to form 3 (Scheme 2). A rate constant
ratio of kaz/kalk ) 1.0 for partitioning of 1+ was determined
from the yields of the nucleophile adducts 1-N3 and 3,
which are formed from reaction of 1-P F B (2 × 10-5 M)
in the presence of both azide ion and
In recent years there have been extensive studies of
structure-reactivity effects on the reactions of carbenium
ions with alkenes in organic solvents1 and with nucleo-
philic anions and solvent in mixed alcohol/water sol-
vents.2 The nucleophilic reactivity of the solvent water
has been estimated to be lower than the reactivity of the
strongly activated alkene pyrrole toward addition to
resonance-stabilized carbocations.1b However, this esti-
mate is based upon a comparison of data for the reaction
of these nucleophiles with different electrophiles in
different solvents. We are not aware of any direct
determination of the relative nucleophilicity of alkenes
and inorganic anions toward carbenium ions in nucleo-
philic solvents, and it is not known whether alkenes can
compete effectively with the large concentrations of these
solvents to give significant yields of an alkene adduct.
We report that 1+ (Scheme 1) exhibits a large selectiv-
ity for reaction with the strongly activated alkene 2 and
a direct comparison of the nucleophilicities of 2 and the
inorganic nucleophile azide ion toward this electrophile.
The reaction of 1-P F B (10-4 M, PFB ) pentafluo-
robenzoate) in 50/50 (v/v) trifluoroethanol/water (I ) 0.50,
NaClO4) gives the following products: the solvent ad-
ducts 1-OSolv, 42% (38% 1-OH and 4% 1-OCH2CF 3);
the cyclization product 2, 5%; and the dimeric product
3, 53%. The addition of 1 mM NaN3 does not affect the
-
kaz/ks ) [1-N3]/[1-OSolv][N3
]
(1)
the alkene 2. It is not known if the rate constants for
reaction of these two nucleophiles with 1+ are identical
because both reactions take place at the diffusion-
controlled limit or because there is a coincidental equality
of the barriers to two activation-limited reactions.
The rate constant ratio ks/kc for partitioning of 1+
between nucleophilic addition of solvent (ks, Scheme 1)
and intramolecular addition of the thioamide sulfur to
the aromatic ring (kc) is equal to the ratio of the yields of
the products of the solvolysis (1-OH + 1-OSolv) and the
cyclization (2 + 3) reactions. These rate constants are
closely matched for reaction in 50/50 (v/v) trifluoroetha-
nol/water ([1-OH + 1-OSolv]/[2 + 3] ) ks/kc ) 0.74), but
in the more nucleophilic solvent of 50/50 (v/v) methanol/
water 2 and 3 are minor reaction products, so that ks .
kc.
In summary, we have shown that (1) at a concentration
of 1.0 M, the alkene 2, which is strongly activated for
nucleophilic attack by electron-donating nitrogen and
sulfur substituents, is 70 000-fold more reactive than the
nucleophilic solvent 50/50 (v/v) methanol/water toward
an electrophilic cation, and (2) the nucleophilic reactivity
of the activated alkene 2 is the same as that of the highly
reactive inorganic nucleophile azide ion. In addition, we
now have in hand an experimental protocol that allows
for the direct comparison of the reactivities of other
alkenes and anionic nucleophiles toward electrophiles in
strongly nucleophilic solvents.
observed first-order rate constant (kobsd ) 4.2 × 10-3 s-1
)
for reaction of 1-P F B, but it causes a change in the
reaction products to a quantitative yield of the azide ion
adduct 1-N3 (Scheme 1). By contrast, the reaction of 5
× 10-5 M 1-P F B in 50/50 (v/v) methanol/water (I ) 0.50,
NaClO4) gives a 98% total yield of the solvent adducts
1-OH (30%) and 1-OMe (68%), only 2% of 3, and no
detectable 2.
We know of no precedent for the observed “self-
assembly” of 3 by reaction of a very low concentration of
1-P F B via heterolytic pathways in a protic, nucleophilic
solvent. All of the rate and product data for these
reactions are consistent with the mechanism shown in
Scheme 1. The reaction of 1-P F B in 50/50 (v/v) trifluo-
roethanol/water is kinetically zero order in the concen-
tration of azide ion, and all of the products of this reaction
are formed by partitioning of a common intermediate, 1+,
which undergoes quantitative trapping by 1 mM azide
ion. This intermediate is either the open R-thioamide-
substituted carbenium ion, a cyclic closed ion, or an
equilibrium mixture of the two (Scheme 1).3 We favor
Exp er im en ta l Section
Syn th esis. 1H NMR spectra were recorded at 200 MHz on a
Varian Gemini spectrometer at the University of Kentucky or
at 300 or 400 MHz on Varian instruments at the University at
Buffalo. Chemical shifts are reported downfield of an internal
* To whom correspondence should be addressed. Tel: (716) 645-
6800 ext. 2194. Fax: (716) 645-6963. E-mail: jrichard@acsu.buffalo.edu.
(1) (a) Mayr, H. Angew. Chem., Int. Ed. Engl. 1990, 29, 1371-1384.
(b) Mayr, H; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957.
(2) (a) McClelland, R. A. Tetrahedron 1996, 52, in press. (b) Richard,
J . P. Tetrahedron 1995, 51, 1535-1573.
(3) Lien, M. H.; Hopkinson, A. C. J . Am. Chem. Soc. 1988, 110,
3788-3792.
(4) (a) Creary, X.; Aldridge, T. E. J . Org. Chem. 1988, 53, 3888-
3890. (b) Creary, X.; Hatoum, H. N.; Barton, A.; Aldridge, T. E. J . Org.
Chem. 1992, 57, 1887-1897.
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