Solvolyses of 2-Deoxy-α- and β-D-Glucopyranosyl 4′-Bromoisoquinolinium Tetrafluoroborates

Article abstract of DOI:10.1021/jo0004106

The solvolyses of 2-deoxy-α- and β-D-glucopyranosyl 4′-bromoisoquinolinium tetrafluoroborates (1 and 2) were monitored in aqueous methanol, ethanol, trifluoroethanol, and binary mixtures of ethanol and trifluoroethanol. The observed rate constants are consistent with the solvolyses of 1 and 2 proceeding via dissociative (D_N * A_N) transition states. In comparison to the α-anomer, solvolysis of the β-compound gives a greater transition state charge delocalization onto the ring oxygen atom. Analysis of the solvolysis product ratios indicates that the 2-deoxyglucosyl oxacarbenium ion is not solvent-equilibrated in the solvent mixtures studied. In the solvolysis of compound 1, the solvent trifluoroethanol facilitates diffusional separation of the leaving group and, in so doing, promotes the formation of the retained trifluoroethyl glycoside.

Full text of DOI:10.1021/jo0004106

J . Org. Chem. 2000, 65, 4423-4430
4423
Solvolyses of 2-Deoxy-r- a n d â-D-Glu cop yr a n osyl
4′-Br om oisoqu in olin iu m Tetr a flu or obor a tes
J iang Zhu and Andrew J . Bennet*
Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, British Columbia V5A 1S6, Canada
bennet@sfu.ca
Received March 21, 2000
The solvolyses of 2-deoxy-R- and â-D-glucopyranosyl 4′-bromoisoquinolinium tetrafluoroborates
(1 and 2) were monitored in aqueous methanol, ethanol, trifluoroethanol, and binary mixtures of
ethanol and trifluoroethanol. The observed rate constants are consistent with the solvolyses of 1
and 2 proceeding via dissociative (DN * AN) transition states. In comparison to the R-anomer,
solvolysis of the â-compound gives a greater transition state charge delocalization onto the ring
oxygen atom. Analysis of the solvolysis product ratios indicates that the 2-deoxyglucosyl oxacar-
benium ion is not solvent-equilibrated in the solvent mixtures studied. In the solvolysis of compound
1, the solvent trifluoroethanol facilitates diffusional separation of the leaving group and, in so doing,
promotes the formation of the retained trifluoroethyl glycoside.
In tr od u ction
(KIE, k12C/k13C) data, the hydrolysis of R-D-glucopyranosyl
fluoride occurs via an “exploded” SN2 transition state.8
Despite the apparent simplicity of nucleophilic substi-
tution at acetal and ketal centers, deciphering the
intimate mechanistic details of these reactions continues
to be an ongoing research goal.1 Historically, it was
considered that the specific acid-catalyzed hydrolysis of
glycopyranosides occurs with unassisted, rate-limiting,
exocyclic C-O bond cleavage of the protonated glycoside
to generate a solvent-equilibrated, cyclic oxygen-stabi-
lized carbocationic intermediate and a neutral alcohol.2,3
Yet the hydrolyses of methoxymethyl derivatives proceed
through so-called “exploded” associative transition states
in which there are weak bonding interactions to both the
nucleophile (nuc) and the leaving group (lg).4,5 In 1991,
Banait and J encks reported that, in water, R-D-glucopy-
ranosyl fluoride reacts via a concerted ANDN (SN2) mech-
anism.6 Furthermore, these authors noted that in aque-
ous methanol (up to 90% v/v MeOH) the only observed
carbohydrate product was glucose.6 This unprecedented
selectivity for water in a nucleophilic substitution reac-
tion must arise from a stringent transition state require-
ment for water to act as the nucleophile, perhaps with
general-base catalysis from a second molecule of solvent.
In a more recent study, Zhang et al.7 concluded that,
based on measured anomeric carbon kinetic isotope effect
In contrast to the above mechanistic picture for R-D-
glucopyranosyl fluoride (3), recent studies by Bennet and
co-workers concluded that nucleophilic substitution reac-
tions of 2-deoxy-R- and â-D-glucopyranosyl 4′-bromoiso-
quinolinium salts (1 and 2) occur via solvent-separated
ion-molecule complexes, involving a stepwise DN * AN
mechanism.9
The anomeric 4′-bromoisoquinolinium salts (1 and 2),
which are models for O-protonated glycosides, react to
form nonconformationally equilibrated diastereomeric
intermediates that are captured by solvent approximately
2-fold more readily on the R- than on the â-face.9 From
their data, Bennet and co-workers estimated that the
lifetimes for the two diastereomeric 2-deoxyglucopyran-
osyl oxacarbenium ions in water are between ∼1.4 ×
10-11 and 2.7 × 10-11 s.9b,10 After correcting these data
for the effect of the 2-hydroxyl group,11 an estimated
lifetime of between 3.5 × 10-12 and 6.8 × 10-12 s is
* To whom correspondence should be addressed. Tel: (604) 291-
3532. Fax: (604) 291-3765.
(1) For some recent examples, see: Liras, J . L.; Lynch, V. M.; Anslyn,
E. V. J . Am. Chem. Soc. 1997, 119, 8191-8200. Horenstein, B. A.;
Bruner, M. J . Am. Chem. Soc. 1996, 118, 10371-10379. J agannadham,
V.; Amyes, T. L.; Richard, J . P. J . Am. Chem. Soc. 1993, 115, 8465-
8466.
(2) Capon, B. Chem. Rev. 1969, 69, 407-498.
(3) Bennet, A. J .; Sinnott, M. L. J . Am. Chem. Soc. 1986, 108, 7287-
7294.
(4) Craze, G-A.; Kirby, A. J .; Osborne, R., J . Chem. Soc., Perkin
Trans. 2 1978, 357-368.
(8) Melander, L.; Saunder, W. H. Reaction Rates of Isotopic Mol-
ecules; Wiley Interscience: New York, 1980; pp 235-248.
(9) (a) Huang, X.; Surry, C.; Hiebert, T.; Bennet, A. J . J . Am. Chem.
Soc. 1995, 117, 10614-10621. (b) Zhu, J .; Bennet, A. J . J . Am. Chem.
Soc. 1998, 120, 3887-3893.
(5) Knier, B. L.; J encks, W. P. J . Am. Chem. Soc. 1980, 102, 6789-
6798.
(6) Banait, N. S.; J encks, W. P. J . Am. Chem. Soc. 1991, 113, 7951-
7958.
(7) Zhang, Y.; Bommuswamy, J .; Sinnott, M. L. J . Am. Chem. Soc.
1994, 116, 7557-7563.
(10) The quoted kSOH values in refs 9b (p 3892) are 2-fold too large,
although the quoted lifetimes (1/kSOH) are correct.
10.1021/jo0004106 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/16/2000

4424 J . Org. Chem., Vol. 65, No. 14, 2000
Zhu and Bennet
obtained for the glucosyl cation, a value that is slightly
larger than the lifetime of 1 × 10-12 s predicted by Amyes
and J encks.11
In 1980, Sinnott and J encks observed that solvolysis
of several glucopyranosyl derivatives generated products
that depended on both the identity of the leaving group
and the anomeric configuration of the starting material.12
From their study, Sinnott and J encks concluded that no
solvent-equilibrated intermediates were formed in the
reactions. Recently, a semiempirical approach was used
to calculate the kinetic and thermodynamic stabilities of
pyranosyl oxacarbenium ions generated from pyridini-
um13 and protonated methyl glycosides.14 However, when
the semiempirical results were compared with those from
published kinetic data of reactions in solution, these
researchers were unable to interpret whether the cyclic
oxacarbenium ion produced during the reactions of
glycopyranosyl pyridinium ions is formed as a solvent-
equilibrated species or as an element of an ion-neutral
complex.13,14
The present report addresses the question of whether
the 2-deoxyglucosyl oxacarbenium ion becomes a solvent-
equilibrated intermediate when the solvolysis reactions
are run in the absence of good nucleophiles such as azide.
To this end, rate constant data and product study results
are presented for the solvolysis of the two anomeric
2-deoxyglucosyl 4′-bromoisoquinolinium tetrafluorobo-
rates (1 and 2) in aqueous mixtures of methanol, ethanol,
and trifluoroethanol, as well as in binary combinations
of ethanol and trifluoroethanol.
F igu r e 1. Plot of log(kobs) versus percent water (v/v) for
solvolysis of 1 (9) and 2 (1) in ethanol/water mixtures, T )
65 °C. Error limits are encompassed within the symbol
diameter.
by nonlinear least-squares regression of the absorbance versus
time data to a standard first-order rate equation.
P r od u ct Stu d ies. The solvolytic product studies were
performed by heating for 10 × t1/2hyd at 65 °C a sealed vial
that contained a solution of the 4-bromoisoquinolinium salt
(1.25 mg/mL) and N-methylmorpholine (0, 1, 2, or 3 equiv) in
a binary solvent mixture (0.50 mL). After cooling, the reaction
vial was opened and a solution of the internal standard methyl
R-D-glucopyranoside in methanol (8 µL, 5.0 mg/mL) was added.
Removal of the solvent under reduced pressure afforded a solid
residue, which was dried under vacuum (∼0.01 mmHg)
overnight. After derivatization of the carbohydrate products
with a standard silylating reagent,18 the resultant solution was
analyzed using GC as detailed in the Supporting Information.
All GC product yields were calculated using a standard
calibration curve.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Ethanol and methanol were dried
by distillation from their respective magnesium alkoxide salts,
while 2,2,2-trifluoroethanol (TFE) was dried by distillation
from anhydrous calcium sulfate and sodium carbonate. Deion-
ized water was further purified by use of a “Milli-Q ultra pure
water” system. NMR spectra were acquired at operating
frequencies of 400 and 100 MHz for 1H and 13C NMR,
respectively, using either CDCl3 or D2O as the solvent and
internal reference. Coupling constants are reported in hertz,
and melting points are uncorrected. 2-Deoxy-R-D-glucopyran-
osyl 4′-bromoisoquinolinium tetrafluoroborate (1)9,15 and 1,6-
anhydro-2-deoxy-â-D-glucopyranose (5)17 were made using
previously published methods. Full synthetic details for the
synthesis of methyl-, ethyl-, and trifluoroethyl 2-deoxy-R- and
â-D-glucopyranosides and 2-deoxy-â-D-glucopyranosyl 4′-bro-
moisoquinolinium tetrafluoroborate (2) are given in the Sup-
porting Information.
Kin etics. The solvolysis reactions of compounds 1 and 2
(∼2 × 10-4 M) were conducted at 65 °C and were monitored
by following the decrease in absorbance at 337 nm using a
Cary 3E UV-vis spectrophotometer equipped with the Cary
six-cell Peltier constant-temperature accessory. Reactions were
initiated by the injection of a stock solution of 1 and 2 (5 µL,
40 mM) into a binary solvent mixture (1.00 mL) containing
N-methylmorpholine (3 equiv). Rate constants were calculated
Resu lts
The solvolysis reactions of the anomeric salts (1 and
2) were run in aqueous mixtures of methanol, ethanol,
and trifluoroethanol and in binary combinations of etha-
nol and trifluoroethanol and were monitored by UV-vis
spectroscopy. All solvolysis reactions in this study were
performed without the addition of ionic strength adjust-
ing salts due to the observation that even if the ionic
strength is held constant, the reaction products for
hydrolysis of 1 and 2 still vary with added salts.9
Furthermore, to minimize perturbations caused by ion-
pair complexes, both anomeric cations (1 and 2) were
synthesized with the nonnucleophilic tetrafluoroborate
counterion.
Listed in Tables S1 and S2 (Supporting Information)
are the observed first-order rate constants for the aque-
ous alcoholysis at 65 °C of 1 and 2. Table S3 (Supporting
Information) details the corresponding rate constants for
the reactions of 1 and 2 in ethanol/trifluoroethanol
mixtures. A representative plot of the rate constant data
for solvolysis of 1 and 2 in aqueous ethanol is shown in
Figure 1.
(11) Amyes, T. L.; J encks, W. P. J . Am. Chem. Soc. 1989, 111, 7888-
7900.
(12) Sinnott, M. L.; J encks, W. P. J . Am. Chem. Soc. 1980, 102,
2026-2032.
(13) Buckley, N. Oppenheimer, N. J . J . Org. Chem. 1996, 61, 8039-
8047.
Figure 2 presents a plot of log(kobs/k0)R versus log(kobs
/
(14) Buckley, N. Oppenheimer, N. J . J . Org. Chem. 1996, 61, 8048-
8062.
k0)â, where k0 is the observed rate constant in 80:20 v/v
EtOH/H2O. From the best linear fit to the data (Figure
(15) The IUPAC name for 2-deoxy-D-glucose is 2-deoxy-D-arabino-
hexose (ref 16).
(16) McNaught, A. D. Pure Appl. Chem. 1996, 68, 1919-2008.
(17) Leteux, C.; Veyrieres, A.; Robert, F. Carbohydr. Res. 1993, 242,
119-130.
(18) Sweeley, C. C.; Bentley, R.; Makita, M.; Wells, W. W. J . Am.
Chem. Soc. 1963, 85, 2497-2507.

Solvolyses of 2-Deoxyglucosyl 4′-Bromoisoquinolinium Salts
J . Org. Chem., Vol. 65, No. 14, 2000 4425
F igu r e 4. Plot of Grunwald-Winstein correlation for the
solvolysis of 1 versus Y+ in MeOH/H2O (2), EtOH/H2O (b),
TFE/H2O (O), and TFE/EtOH (4) mixtures at T ) 65 °C. The
line shown is the best linear least-squares fit through the data
points.
F igu r e 2. Plot of log(kobs/k0)R versus (kobs/k0)â for solvolysis of
1 and 2 in ethanol/water mixtures, T ) 65 °C. The line shown
is the best linear least-squares fit through the data points.
F igu r e 3. Plot of log(kobs/k0)R versus (kobs/k0)â for solvolysis of
1 and 2 in trifluoroethanol/water mixtures, T ) 65 °C.
F igu r e 5. Plot of Grunwald-Winstein correlation for the
solvolysis of 2 versus Y+ in MeOH/H2O (2), EtOH/H2O (b),
TFE/H2O (O), and TFE/EtOH (4) mixtures at T ) 65 °C. The
line shown is the best linear least-squares fit through the data
points.
2), the apparent linear correlation indicates that the
change in polarity of the EtOH/H2O solvent mixture has
a similar, but slightly smaller effect on the solvolytic rate
of the R-anomer (1) relative to that of the â-anomer (2).
This difference can be quantified by the use of eq 1, where
S is a sensitivity parameter.
log(kobs/k0) ) mYX
(2)
When the kinetic data given in Tables 1-3 is fit to eq
2 using Y+ values that were calculated from the solvolysis
of 1-adamantyl dimethylsulfonium triflate (70.4 °C),20,21
the derived m values are -3.64 ( 0.34 and -4.78 ( 0.33
for the reactions of 1 and 2, respectively. Figures 4 and
5 display the Grunwald-Winstein plots for the solvolyses
of 1 and 2.
To ensure that the alkyl 2-deoxyglucoside products are
stable to the solvolytic conditions, all product studies on
the solvolysis reactions of 1 and 2 were performed in the
presence of 1 molar equiv of N-methylmorpholine. The
products as well as the respective quantities of each
product formed during the solvolysis of 1 and 2 were
identified by standard GC analysis. Given in Tables S4-
S12 (Supporting Information) are the measured product
percentages and yields for the solvolytic reactions of 1
and 2. In addition, to ensure that the solvolysis reactions
log(kobs/k0)R ) S log(kobs/k0)â + constant
(1)
The derived values of S (eq 1) for solvolysis of 1 and 2 in
MeOH/H2O, EtOH/H2O, and EtOH/TFE mixtures are
0.934 ( 0.008, 0.906 ( 0.023, and 0.779 ( 0.003,
respectively. In Figure 3 by contrast, a similar plot for
the solvolytic reactions of 1 and 2 in TFE/H2O displays
a marked nonlinearity.
The standard Grunwald-Winstein equation (eq 2) is
commonly used to analyze solvent effects on rate con-
stants for DN + AN (SN1) substitution reactions, where
the YX parameter is a measure of the solvent’s ionizing
power and m is a sensitivity variable.19
(19) (a) Grunwald, E.; Winstein, S. J . Am. Chem. Soc. 1948, 70, 846-
854. (b) Fainberg, A. H.; Winstein, S. J . Am. Chem. Soc. 1956, 78,
2770-2777. (c) Schadt, F. L.; Schleyer, P. v. R. J . Am. Chem. Soc. 1973,
95, 7860-7862. (d) Bentley, T. W.; Schadt, F. L.; Schleyer, P. v. R. J .
Am. Chem. Soc. 1972, 94, 992-995. (e) Schadt, F. L.; Bentley, T. W.;
Schleyer, P. v. R. J . Am. Chem. Soc. 1976, 98, 7667-7674. (f) Bentley,
T. W.; Schleyer, P. v. R. Adv. Phys. Org. Chem. 1977, 14, 32-40. (g)
Bentley, T. W.; Llewellyn, G. Prog. Phys. Org. Chem. 1990, 17, 121-
158.
(20) Kevill, D. N.; Anderson, S. W. J . Am. Chem. Soc. 1986, 108,
1579-1585.
(21) The Y+ values for aqueous trifluoroethanol (v/v) were interpo-
lated from the values given in ref 20 that were measured using a
weight-weight basis.

4426 J . Org. Chem., Vol. 65, No. 14, 2000
Zhu and Bennet
Ta ble 1. P r od u ct Distr ibu tion fr om th e Solvolyses of Com p ou n d s 1 a n d 2 in Aqu eou s Meth a n ol (v/v) a t 65 °C
a
a
MeOH
(kMeOH/kHOH
)
1
stereoselectivity1
(kMeOH/kHOH
)
2
stereoselectivity2
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
2.86 ( 0.08
2.82 ( 0.05
2.49 ( 0.08
2.25 ( 0.05
2.08 ( 0.03
1.92 ( 0.06
1.80 ( 0.08
1.70 ( 0.06
1.70 ( 0.12
1.65 ( 0.11
17.5 ( 1.1
16.9 ( 0.7
15.3 ( 0.7
14.1 ( 0.4
11.3 ( 1.4
12.8 ( 0.6
10.7 ( 0.5
9.7 ( 0.7
8.2 ( 3.0
NIb
1.22 ( 0.03
1.19 ( 0.03
1.21 ( 0.02
1.32 ( 0.01
1.35 ( 0.02
1.42 ( 0.03
1.43 ( 0.02
1.53 ( 0.04
1.73 ( 0.05
0.89 ( 0.01
0.89 ( 0.02
0.95 ( 0.01
0.94 ( 0.10
1.07 ( 0.02
1.11 ( 0.02
1.18 ( 0.05
1.30 ( 0.05
1.39 ( 0.09
a
b
[Inverted glycoside]/[Retained glycoside]; see eq 4. NI ) not integrated; estimated that less than 0.7% methyl 2-deoxy-â-D-
glucopyranoside was formed.
Ta ble 2. P r od u ct Distr ibu tion fr om th e Solvolyses of Com p ou n d s 1 a n d 2 in Aqu eou s Eth a n ol (v/v) a t 65 °C
a
a
EtOH
(kEtOH/kHOH
)
1
stereoselectivity1
(kEtOH/kHOH
)
2
stereoselectivity2
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
3.98 ( 0.19
3.53 ( 0.20
2.87 ( 0.18
2.48 ( 0.12
2.28 ( 0.19
2.11 ( 0.12
2.01 ( 0.09
1.96 ( 0.08
2.06 ( 0.16
2.32 ( 0.09
11.4 ( 0.4
10.1 ( 0.4
9.2 ( 0.2
8.2 ( 0.2
7.4 ( 0.3
6.7 ( 0.3
6.7 ( 1.3
NIb
0.61 ( 0.03
0.60 ( 0.03
0.64 ( 0.02
0.75 ( 0.04
0.82 ( 0.03
0.91 ( 0.03
0.95 ( 0.02
1.11 ( 0.07
1.31 ( 0.03
0.41 ( 0.02
0.42 ( 0.01
0.45 ( 0.01
0.49 ( 0.01
0.54 ( 0.01
0.57 ( 0.03
0.53 ( 0.01
0.58 ( 0.01
0.68 ( 0.02
NDc
NDc
a
b
[Inverted glycoside]/[Retained glycoside]; see eq 4. NI ) not integrated; estimated that less than 0.9% ethyl 2-deoxy-â-D-
glucopyranoside was formed. c ND ) not detected; no peak for ethyl 2-deoxy-â-D-glucopyranoside was observed.
Ta ble 3. P r od u ct Distr ibu tion fr om th e Solvolyses of Com p ou n d s 1 a n d 2 in Aqu eou s Tr iflu or oeth a n ol (v/v)
a t 65 °C
a
a
TFE
(kTFE/kHOH
)
1
stereoselectivity1
(kTFE/kHOH
)
2
stereoselectivity2
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0.43 ( 0.05
0.42 ( 0.02
0.42 ( 0.01
0.43 ( 0.08
0.48 ( 0.05
0.54 ( 0.05
0.50 ( 0.20
0.53 ( 0.14
NIb
1.40 ( 0.17
2.96 ( 0.19
4.45 ( 0.14
4.64 ( 0.49
4.19 ( 0.13
3.40 ( 0.17
NIb
0.51 ( 0.05
0.53 ( 0.01
0.60 ( 0.06
0.49 ( 0.03
0.39 ( 0.02
0.36 ( 0.06
0.37 ( 0.04
0.30 ( 0.03
0.27 ( 0.18
0.18 ( 0.01
0.16 ( 0.01
0.17 ( 0.01
0.18 ( 0.01
0.18 ( 0.01
0.16 ( 0.01
0.18 ( 0.01
0.20 ( 0.01
NIb,c
NIb
NIb
NIb
NIb,c
a
b
[Inverted glycoside]/[Retained glycoside]; see eq 4. NI ) not integrated; estimated that less than 0.6% trifluoroethyl 2-deoxy-â-D-
glucopyranoside was formed. c NI ) not integrated; estimated that less than 0.3% trifluoroethyl 2-deoxy-R-D-glucopyranoside was formed.
are not being catalyzed by the added base N-methylmor-
pholine, product studies were performed using various
concentrations of base in alcoholic solvents. Tables S13-
S18 list the measured product percentages and yields for
the solvolytic reactions of 1 and 2 at various concentra-
the observed product ratios for solvolysis of 1 and 2 in
aqueous mixtures of methanol, ethanol, and trifluoro-
ethanol. Tables 4 and 5 list the nucleophilic selectivities
and stereoselectivities for the solvolysis reactions of 1 and
2 run in EtOH/TFE mixtures, as well as in a solvent
mixture of EtOH/TFE/H2O (5:45:50, v/v).
tions of N-methylmorpholine.
Nucleophilic selectivity (kROH/kR′OH
22
)
is calculated ac-
cording to eq 3, using the observed product ratios and
the nucleophile concentrations. Stereoselectivity for a
single nucleophile is calculated from the ratio of inverted
to retained products (eq 4).
Discu ssion
The concentration of pyridinium salt (1 or 2) used in
the product studies is about 14-fold greater than that
used in the kinetic experiments (2.83 vs 0.2 mM).
General-base catalysis is obviously not involved in the
solvolysis reactions of 1 and 2 in methanol and ethanol,
since the products formed are invariant when up to at
least 2 equiv of base is added to the solvolytic medium
(Tables S13-S16).23 In addition, the quantities of prod-
ucts formed in trifluoroethanol-containing solvents re-
main invariant at lower concentrations of N-methylmor-
pholine, while 2-3 equiv generate a greater amount of
trifluoroethyl glycosides at the expense of glucal 4 and
kROH
[Gly-OR][R′OH]
[Gly-OR′][ROH]
)
(3)
(4)
kR′OH
[Gly-OR]inv
[Gly-OR]ret
Stereoselectivity )
Compiled in Tables 1-3 are the nucleophilic selectivi-
ties (kROH/kHOH) and the stereoselectivities calculated from
(22) Ta-Shma, R.; Rappoport, Z. Adv. Phys. Org. Chem. 1992, 27,
239-291.
(23) These observations also rule out the possibility that N-meth-
ylmorpholine could act as a nucleophile.

Solvolyses of 2-Deoxyglucosyl 4′-Bromoisoquinolinium Salts
J . Org. Chem., Vol. 65, No. 14, 2000 4427
Ta ble 4. P r od u ct Distr ibu tion fr om th e Solvolyses of 1 in EtOH/TF E a t 65 °C
a
a
TFE
(kEtOH/kTFE
)
ret
(kEtOH/kTFE
)
inv
(stereoselectivity)TFE
(stereoselectivity)EtOH
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0.43 ( 0.05
0.37 ( 0.05
0.39 ( 0.06
0.41 ( 0.05
0.44 ( 0.08
0.44 ( 0.02d
0.48 ( 0.05
0.53 ( 0.03
0.58 ( 0.04
NIf
15.1 ( 0.9
12.4 ( 1.5
10.9 ( 1.0
9.4 ( 0.9
49.6 ( 6.4
38.3 ( 4.6
32.4 ( 2.8
25.5 ( 3.8
1.21 ( 0.05
1.21 ( 0.06
1.21 ( 0.06
1.20 ( 0.03
1.21 ( 0.04e
1.22 ( 0.05
1.22 ( 0.02
1.23 ( 0.06
1.23 ( 0.05
3.98 ( 0.19
2.60 ( 0.09
8.7 ( 0.3b
8.0 ( 0.8
6.6 ( 0.3
5.1 ( 0.3
5.3 ( 0.4
24.0 ( 0.9c
20.5 ( 1.0
15.3 ( 0.5
10.7 ( 0.5
NIf
ETWg
2.14 ( 0.08
10.6 ( 0.4
0.53 ( 0.02
a
b
[Inverted glycoside]/[Retained glycoside]; see eq 4. The value for solvolysis of R-D-glucopyranosyl 4′-methylpyridinium triflate in
56% v/v TFE/EtOH is 2.0 ( 0.2.12 c The value for solvolysis of R-D-glucopyranosyl 4′-methylpyridinium triflate in 56% v/v TFE/EtOH is
9.3 ( 1.3.12 The value for solvolysis of R-D-glucopyranosyl 4′-methylpyridinium triflate in 56% v/v TFE/EtOH is 0.83 ( 0.1312 e The
d
value for solvolysis of R-D-glucopyranosyl 4′-methylpyridinium triflate in 56% v/v TFE/EtOH is 3.8 ( 0.2.12 f NI ) not integrated; estimated
g
that less than 0.2% trifluoroethyl 2-deoxy-â-D-glucopyranoside was formed. Solvent ETW is 5:45:50 v/v/v EtOH/TFE/H2O.
Ta ble 5. P r od u ct Distr ibu tion fr om th e Solvolyses of 2 in EtOH/TF E a t 65 °C
a
a
TFE
(kEtOH/kTFE
)
Ret
(kEtOH/kTFE
)
inv
(stereoselectivity)TFE
(stereoselectivity)EtOH
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1.40 ( 0.17
1.71 ( 0.10
2.21 ( 0.14
3.02 ( 0.16
3.79 ( 0.20
4.7 ( 0.4d
4.7 ( 0.6
NIf
8.0 ( 0.6
7.2 ( 0.5
7.3 ( 0.4
7.0 ( 0.3
8.2 ( 0.4
7.8 ( 0.4
8.0 ( 0.3
8.1 ( 0.3
1.76 ( 0.11
2.39 ( 0.15
3.32 ( 0.12
4.38 ( 0.08
5.70 ( 0.10e
7.23 ( 0.11
9.24 ( 0.16
10.9 ( 0.14
13.1 ( 0.2
7.0 ( 0.5b
5.8 ( 0.7
NIf
8.5 ( 0.2c
8.8 ( 0.2
9.5 ( 0.3
9.7 ( 0.2
10.5 ( 2.2
NDg
NDg
NDg
NDg
11.4 ( 0.4
ETWh
5.49 ( 0.92
4.14 ( 0.50
3.40 ( 0.20
2.56 ( 0.51
a
b
[Inverted glycoside]/[Retained glycoside]; see eq 4. The value for solvolysis of â-D-glucopyranosyl 3′-bromopyridinium triflate in 56%
v/v TFE/EtOH is 13 ( 7.12 c The value for solvolysis of â-D-glucopyranosyl 3′-bromopyridinium triflate in 56% v/v TFE/EtOH is 4.5 (
0.4.12 The value for solvolysis of â-D-glucopyranosyl 3′-bromopyridinium triflate in 56% v/v TFE/EtOH is 11 ( 3.12 e The value for
d
solvolysis of â-D-glucopyranosyl 3′-bromopyridinium triflate in 56% v/v TFE/EtOH is 3.8 ( 0.9.12 f NI ) not integrated; estimated that
g
less than 0.1% trifluoroethyl 2-deoxy-â-D-glucopyranoside was formed. ND ) not detected; no peak for trifluoroethyl 2-deoxy-â-D-
h
glucopyranoside was observed. Solvent ETW is 5:45:50 v/v/v EtOH/TFE/H2O.
Sch em e 1
diffusional separation of the pyridine from the IMC
complex can occur, giving a solvent-separated ion-
molecule complex (Scheme 1, pathway b). At this point,
the solvent-separated IMC can partition in one of two
ways. Solvent can capture the IMC on either of its two
diastereomeric faces, as shown in Scheme 1, pathway c,
or the IMC can give an oxacarbenium ion intermediate
(Scheme 1, pathway d ), which is then captured by solvent
to give both retained and inverted products (Scheme 1,
pathway e).
Ra tes of Solvolysis. Since positively charged glycosyl
pyridinium salts hydrolyze via transition states having
significant C-N bond cleavage,9,24,25 it is expected that
a small increase in the solvolysis rate constant would be
associated with a decrease in polarity of the solvent.26
Accordingly, in the binary solvent mixtures MeOH/H2O,
EtOH/H2O (Figure 1), and EtOH/TFE, the observed
solvolytic rate constants for both 1 and 2 increase in
response to a solvent mixture containing a decreased
fractional composition of the more polar solvent. It is
notable that the relative increase in rate constant for the
â-anomer (2) is larger than that for the diastereomeric
R-anomer (1).
1,6-anhydro-2-deoxy-â-D-glucopyranose (5) (Tables S17
and S18). Therefore, in the current system there is no
kinetically significant, bimolecular, general-base-cata-
lyzed pathway, and given that the observed products are
independent of the addition to the solvolysis medium of
up to 2 equiv of N-methylmorpholine, the product-
forming steps are not base-catalyzed.
In light of the absence of base-catalyzed pathways, the
solvolysis reactions of the diastereomeric 2-deoxy glucosyl
4′-bromoisoquinolinium salts were analyzed in terms of
Scheme 1.9 In this scheme, the first-formed intermediate
is an ion-molecule complex (IMC) which can react
initially in one of two ways to generate the observed
products. It can react to form an inverted solvolysis
product by direct capture of the glucosyl cation by solvent
prior to the dissociation of the pyridine leaving group
from the complex (Scheme 1, pathway a ). Alternatively,
(24) Huang, X.; Tanaka, K. E. S.; Bennet, A. J . J . Am. Chem. Soc.
1997, 119, 11147-11154.
(25) Hosie, L.; Marshall, P. J .; Sinnott, M. L. J . Chem. Soc., Perkin
Trans. 2 1984, 1121-1131.
(26) March, J . Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structure, 4th ed.; Wiley Interscience: New York, 1991;
pp 357-362.

4428 J . Org. Chem., Vol. 65, No. 14, 2000
Zhu and Bennet
Sch em e 2
F igu r e 6. Plot of Grunwald-Winstein correlation for the
solvolysis of 1 (9) and 2 (1) versus Y+tBu in TFE/EtOH mixtures
at T ) 65 °C. The lines shown are the best linear least-squares
fits through the data points (see discussion section for details).
Gr u n w a ld -Win stein Y Sca le. The effect of the
solvent on the rates of DN + AN substitution reactions
can be analyzed using the standard Grunwald-Winstein
equation (eq 2).19 A series of YX scales have been
constructed for a variety of leaving groups (X) in order
to allow for solvent-based electrophilic assistance to
ionization.27 Although it would be ideal to analyze the
kinetic data for the two anomeric 2-deoxyglucosides using
decrease in the importance of TS solvation relative to
solvation of the positively charged GS, and this results
in the observation of an inverted trend for the effect of
solvent on the hydrolysis rate constants. This inversely
related reactivity pattern was observed by Kevill and
Anderson for the solvolyses of tert-butyl and 1-adamantyl
dimethylsulfonium triflates in binary mixtures of TFE
and EtOH (Scheme 2b,c).20,28 In the present study,
solvolysis of 1 and 2 generates oxacarbenium ions in
which the charge can be more extensively delocalized
than in the case of the tert-butyl cation. This results in
a more pronounced decrease in the observed reaction rate
in response to an increase in the solvent polarity. When
the solvolysis data for 1 and 2 (Table S3) are fit to the
Grunwald-Winstein equation using Y+ values that were
a Y+ scale, insufficient kinetic data are available for
Pyr
the establishment of a pyridine leaving group-based scale
due to the extremely sluggish nature of the solvolysis
reactions of 1-adamantyl pyridinium perchlorate.28,29 As
a result, the effect of solvent on the hydrolytic rate
constants for 1 and 2 is analyzed using Kevill and
Anderson’s Y+ scale, which is derived from the rates of
solvolysis for 1-adamantyl dimethylsulfonium triflate.20
The derived m values for the solvolysis of 1 and 2 are
-3.64 ( 0.34 and -4.78 ( 0.33, respectively (Figures 4
and 5). The negative m values measured in the present
study indicate that the effect of solvent on the solvolysis
rate constants for 1 and 2 will be opposite of that reported
for 1-adamantyl dimethylsulfonium triflate.20
It is important to remember that, in the work pre-
sented herein, the leaving group is a neutral molecule.
Therefore, both the ground state (GS) and the transition
state (TS) are positively charged, and as a consequence,
a change in the ionizing power of the solvent could have
a more pronounced effect on either the GS or the TS.
For (4-tert-butyl-1-cyclohexenyl)aryliodonium tetraflu-
oroborates30 and 1-adamantyl dimethylsulfonium triflate
(Scheme 2a,b),20 the solvolytic rates increase in parallel
to increasing ionizing power of the solvent, with the
larger effect observed for the aryliodonium salts. For
these two compounds, positive charge localization occurs
at the respective TS’s onto carbon atoms that will become
either a bent sp-hybridized cyclohexene carbocation as
in the case of the aryliodonium salts or a pyramidalized
sp2-hybridized carbenium ion as occurs for the 1-ada-
mantyl compound. However, as the carbenium ion stabil-
ity increases due to charge delocalization, there is a
+
derived from tBuSMe2 solvolyses,28 m values greater
than 1 are obtained. Specifically, the evaluated m values
are 2.63 ( 0.11 and 3.38 ( 0.14 for the reactions of 1
and 2, respectively (Figure 6). Thus, the observed greater
sensitivity of the solvolysis rates for both 1 and 2 as
compared with tert-butyl dimethylsulfonium triflate re-
sults from greater positive charge delocalization occurring
at the transition states for glycoside hydrolysis.
The larger m value associated with the reactions of 2
as compared to 1 is consistent with greater TS charge
delocalization occurring onto the endocyclic oxygen atom
during solvolysis of the â-anomer. This conclusion is
consistent with the reported ring oxygen kinetic isotope
effects (18O KIEs) for the specific acid-catalyzed hydroly-
ses of methyl glycosides,31,32 where bonding between the
ring oxygen and the anomeric carbon strengthens during
the formation of a cyclic oxacarbenium ion. Greater C-O
double bond character at the transition state results in
a more inverse ring 18O KIE. The measured 18O KIEs for
methyl R-D- and â-D-xylopyranoside are 0.986 ( 0.001
and 0.978 ( 0.001,31 respectively, while the corresponding
values for methyl R-D- and â-D-glucopyranoside are 0.9965
( 0.001 and 0.991 ( 0.002.32
Solvolysis P r od u cts. Since formation of the bicyclic
acetal (5) results from an intramolecular nucleophilic
attack, the solvolysis of both 1 and 2 generates predomi-
nately substitution products (>85%) rather than the
(27) Bentley, T. W.; Bowen, C. T.; Brown, H. C.; Chloupek F. J . J .
Org. Chem. 1981, 46, 38-42.
(28) Kevill, D. N.; Kamil, W. A. J . Org. Chem. 1982, 47, 3785-3787.
(29) The solvolytic rates for 1-adamantylpyridinium perchlorate,
quoted in ref 28, were monitored at 190 °C.
(30) Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J . Am. Chem.
Soc. 1995, 117, 3360-3367.
(31) Indurugalla, D.; Bennet, A. J . Manuscript in preparation.
(32) Bennet, A. J .; Sinnott, M. L. J . Am. Chem. Soc. 1986, 108,
7287-7294.

Solvolyses of 2-Deoxyglucosyl 4′-Bromoisoquinolinium Salts
J . Org. Chem., Vol. 65, No. 14, 2000 4429
of alcoholysis as [ROH] increases; (4) (kROH/kHOH
is
)
1
always greater than (kROH/kHOH)2; and (5) the stereose-
lectivity for the â-anomer is always greater than for the
R-anomer.
Two conclusions can be drawn from the above observa-
tions. First of all, nucleophilic solvation cannot be
important in the solvolysis reactions of 1 and 2. One
would expect to observe vestiges of a nucleophilic solva-
tion effect for the capture of these short-lived (≈2 × 10-11
s), cationic intermediates,9 and as such, this would
translate into increased nucleophilic selectivity (kROH
/
kHOH) in conjunction with reduced solvent polarity (Tables
1-3). In contrast, the observed selectivity is lower in the
less polar, more nucleophilic, alcoholic solvents (EtOH
and MeOH). Second, it can be concluded that the selec-
tivity of the first formed ion-molecule complex9 is
reduced as the fraction of alcohol in the binary solvent
mixture increases. This effect arises from a reduced
ability of the less polar solvent to solvate positive charges,
thereby decreasing the extent of reorganization that
occurs within the IMC prior to solvent capture of the
cationic intermediate.
Solvolyses in Eth a n ol/Tr iflu or oeth a n ol Mixtu r es.
As pointed out by Sinnott and J encks,12 it is expected
that the selectivity ratios (kEtOH/kTFE
)
inv
from competing
SN1 and SN2 reactions would increase as the fraction of
the more nucleophilic, less ionizing solvent ethanol is
increased. Given that the exact opposite trend is observed
during solvolysis of 1, and that no changes are perceived
for the reactions of 2, the following two reasonable
conclusions can be drawn: (1) solvolyses of 1 and 2 occur
via a single dissociative reaction channel; and (2) no
nucleophilic component emerges in ethanol-rich, low-
polarity solvents. This latter conclusion reaffirms the
previously discussed point that there is no significant role
for nucleophilic solvation in these solvolysis reactions.
Recent results from several research groups suggest that
nucleophilic solvation is either unimportant34 or very
weak for dissociative solvolysis reactions in general.35
This can also be applied to six-membered rings where
nucleophilic attack is sterically inhibited.36
Since the addition of 10% TFE to pure EtOH causes a
dramatic change in the observed products arising from
the solvolysis of 1 (but not of 2), trifluoroethanol facili-
tates diffusional separation of the 4-bromoisoquinoline
from the R-anomer in such a way that solvent capture
with retention of configuration is promoted (Figure 7).
However, trifluoroethanol cannot provide electrophilic
assistance to the departure of the neutral pyridine
leaving group by way of the formation of H-bonds during
cleavage of the anomeric C-N bond. This is in contrast
to the situation that occurs for loss of fluoride ion during
the reactions of R-D-glucopyranosyl fluoride.12
F igu r e 7. Plot of the observed product percentages versus
percent trifluoroethanol (v/v) for solvolysis reactions of 1 (filled
symbols) and 2 (open symbols) in ethanol/trifluoroethanol
mixtures: (a) ethyl 2-deoxy-R-D-glucoside (b) and ethyl 2-deoxy-
â-D-glucoside (9); (b) trifluoroethyl 2-deoxy-R-D-glucoside (2)
and trifluoroethyl 2-deoxy-â-D-glucoside ([); (c) D-glucal (1)
and 1,6-anhydro-2-deoxy-â-D-glucopyranose (`); T ) 65 °C.
glucal 4 elimination product. The complete formation of
solvent-equilibrated oxacarbenium ion intermediates can
be ruled out, because for all of the solvent mixtures
investigated, solvolysis of the two anomeric glycosyl salts
gives rise to different product ratios.
Figure 7 displays the product percentages formed
during the reactions of both 1 and 2 in ethanol/trifluo-
roethanol mixtures.33
Solvolyses in Aqu eou s Meth a n ol a n d Eth a n ol.
With respect to the reaction products formed, several
trends can be delineated from the observed product
distributions for the solvolysis reactions of 1 and 2 in
binary mixtures of MeOH/H2O and EtOH/H2O (Tables
1, 2, S4-S5, S8-S9, and S19), including (1) the formation
of more inverted, rather than retained alkyl glycoside;
The substitution reactions of the R-anomer 1 with TFE
primarily give the retained glycoside, while the corre-
(34) (a) Abraham, M. H.; Taft, R. W.; Kamlet, M. J . J . Org. Chem.
1981, 46, 3053-3056. (b) Dvorko, G. F.; Ponomareva, E. A.; Kulik, N.
I. Russ. Chem. Rev. 1984, 53, 547-560. (c) Faˇrcas¸iu, D.; J a˜hme, J .;
Ru¨chardt, C. J . Am. Chem. Soc. 1985, 107, 5717-5722. (d) Katritzky,
A. R.; Brycki, B. E. Chem. Soc. Rev. 1990, 17, 83-105. (e) Richard, J .
P.; Amyes, T. L.; Vontor, T. J . Am. Chem. Soc. 1991, 113, 5871-5873.
(f) Toteva, M. M.; Richard, J . P. J . Am. Chem. Soc. 1996, 118, 11434-
11445.
(35) Richard, J . P.; J agannadham, V.; Amyes, T. L.; Mishima, M;
Tsuno, Y. J . Am. Chem. Soc. 1994, 116, 6706-6712.
(36) (a) Fierens, P. J . C.; Vershelden, P. Bull. Soc. Chim. Belg. 1952,
61, 427-451. (b) Eliel, E. L.; Ro, R. S. J . Am. Chem. Soc. 1957, 79,
5995-6000.
(2) decreased nucleophilic selectivity for alcoholysis (kROH
/
kHOH) as [ROH] increases; (3) increased stereoselectivity
(33) In aqueous EtOH and MeOH solvent mixtures that had a water
content of >20% (v/v), a small (e0.9%) but detectable quantity of 1,6-
anhydro-2-deoxy-â-D-glucopyranose was generated.

4430 J . Org. Chem., Vol. 65, No. 14, 2000
Zhu and Bennet
sponding reactions of 2 afford mainly the inverted
product. With respect to the R-anomer 1, it appears that
a significant fraction of the cationic intermediate that is
trapped by TFE is produced by way of general-base
catalysis by the departing 4-bromoisoquinoline, a process
that must occur at the stage of the solvent-separated IMC
(Scheme 1).
dinium ion gives a significant quantity of 1,6-anhydro-
â-D-glucopyranose.25 In the present study, addition of 3
equiv of N-methylmorpholine causes an increase in the
fraction of trifluoroethyl glycoside formed. Therefore, it
appears that 1,6-anhydro-2-deoxy-â-D-glucose (5) forma-
tion occurs without general-base catalysis and that
formation of a greater amount of 5 in TFE-containing
solvents results from a longer-lived intermediate being
able to attain the required pyranosyl ring conformation
necessary in order for ring closure to occur.
The observed nucleophilic selectivities (kEtOH/kTFE
)
ret
for solvolysis with retention of configuration of com-
pounds 1 and 2 (Tables 4 and 5) are greater than those
observed for the reactions of 1-adamantyl pyridinium
(kEtOH/kTFE ) 1.67; T ) 190 °C) and 1-adamantyl dimeth-
ylsulfonium triflates (kEtOH/kTFE ) 1.10; T ) 40 and 190
°C).37 This selectivity difference could be caused either
by the 1-adamantyl carbenium ion being less stable than
the 2-deoxyglucosyl cation or by the nonplanar 1-ada-
mantyl cation possessing an inherently different reactiv-
ity than planar, delocalized oxacarbenium ions.
Effect of th e 2-OH Gr ou p . Sinnott and J encks
suggested that, due to the greater tendency of â-D-
glucopyranosyl derivatives to solvolyze with overall
inversion of configuration, the 2-OH group might facili-
tate the delivery of a solvent nucleophile via a general-
base-catalyzed pathway.12 The results listed in Table S11
show that, under comparable conditions,38 â-D-glucopy-
ranosyl 3′-bromopyridinium triflate solvolyzes to give
slightly more inverted product than does 2-deoxy â-D-
glucopyranosyl 4′-bromoisoquinolinium tetrafluoroborate.
Therefore, product formation from the 2-deoxy glucosyl
In ter m ed ia te Lifetim es. In 1984, J encks and co-
workers showed that the nucleophilic selectivity (kROH
/
kTFE) for capture of substituted 1-phenylethyl carbenium
ions in mixtures of 5:45:50 (v/v) ROH/TFE/H2O43 de-
creased as the lifetime of the cation, measured in 50:50
(v/v) TFE/H2O, decreased.44 A similar relationship has
been noted for the solvolysis reactions of substituted
cumyl derivatives.34e Using the published values for
nucleophilic selectivity43 and cation lifetime,44 and the
nucleophilic selectivity values listed in Tables 4 and 5,
the computed lifetime for a 2-deoxyglucosyl cation falls
in the range of 1.0 × 10-12 to 3.3 × 10-10 s. Given that
these estimated lifetimes for the 2-deoxyglucosyl oxa-
carbenium ion are extrapolated from lifetime values of
substituted 1-phenylethyl carbenium ions, it is remark-
able that there is agreement between these values and
the previously estimated value of approximately 2.0 ×
10-11 s for the lifetime of the 2-deoxyglucosyl cation in
water. Although this level of consistency might be due
to fortuity, some similarities do exist between 2-deoxy-
glucosyl and 1-phenylethyl carbenium ions. Namely, both
ions are secondary, resonance-stabilized cations, with
electron donation occurring by either an adjacent oxygen
atom or a neighboring aryl group.
compound is associated with a selectivity value (kEtOH
/
kTFE inv approximately 2-fold greater than the correspond-
)
ing value for the glucopyranosyl derivative. These modest
selectivity changes between glucosyl and 2-deoxyglucosyl
derivatives possessing leaving groups with similar pKa’s39
suggest that, in the case of pyridine leaving groups, the
glucosyl 2-OH group is not active in promoting solvent
capture of cationic intermediates.
F or m a tion of Glu ca l. Since the percentage of com-
pound 4 formed during these solvolysis reactions is nearly
independent of the solvent composition (Tables S4, S5,
S8, and S9), glucal formation is likely to occur at the
stage of the ion-molecule complex via a subsequent
deprotonation of the C-2 carbon. A similar conclusion was
reported by Thibblin and Saeki: for the solvolysis of 1-(1-
methyl-1-phenylethyl)pyridinium cations in 25 vol %
acetonitrile in water, the elimination products are formed
with assistance for proton-abstraction provided at the
point of the ion-molecule complex by the leaving group
pyridine.41
Con clu sion s
Solvolyses of 1 and 2 proceed via dissociative (DN * AN)
transition states in which there is no significant nucleo-
philic solvation. In addition, the observed values for the
Grunwald-Winstein sensitivity parameter m are con-
sistent with greater transition state charge delocalization
occurring during solvolysis of the â-anomer. The 2-deoxy-
glucosyl oxacarbenium ion is not solvent-equilibrated in
any of the solvent mixtures studied. Trifluoroethanol
facilitates diffusional separation of the leaving group, and
this results in greater quantities of the substitution
product that has a retained configuration.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the Natural Sciences and Engineering Research
Council of Canada and Simon Fraser University for
financial support of this work. The authors would also
like to thank Dr. T. E. Kitos for editorial assistance with
the manuscript.
F or m a tion of 1,6-An h yd r o-2-d eoxyglu cose. The
products formed during the spontaneous hydrolyses of
1,9b 2,9a R-D-glucopyranosyl 3′-bromopyridinium bro-
mide,25 and â-D-galactopyranosyl 3′-chloropyridinium
bromide42 are the corresponding sugars, whereas in the
presence of base, the R-D-glucopyranosyl 3′-bromopyri-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of 2, methyl-, ethyl-, and trifluoroethyl
2-deoxy-R- and â-glucosides, and for the GC analysis of the
solvolytic products. Complete tables of observed rate constants
and products for the solvolysis reactions of 1 and 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(37) McManus, S. P.; Crutcher, T.; Naumann, R. W.; Tate, K. L.;
Zutaut, S. E; Katritzky, A. R.; Kevill, D. N. J . Org. Chem. 1988, 53,
4401-4403.
(38) The solvolysis studies reported in ref 12 were performed in
equimolar TFE/EtOH, which is equivalent to approximately 56% v/v
TFE/EtOH.
(39) Values taken from ref 40, pKa (3-bromopyridine-H+) ) 2.90 and
J O0004106
pKa (4-bromoisoquinoline-H+) ) 3.31.
(40) Perrin, D. D. Dissociation Constants of Organic Bases in
Aqueous Solution; Butterworths: London, 1965.
(41) Thibblin, A.; Saeki, Y. J . Org. Chem. 1997, 62, 1079-1082.
(42) J ones, C. C.; Sinnott, M. L.; Souchard, I. J . L. J . Chem. Soc.,
Perkin Trans. 2 1977, 1191-1198.
(43) Richard, J . P.; J encks, W. P. J . Am. Chem. Soc. 1984, 106,
1373-1383.
(44) Richard, J . P.; Rothenberg, M. E.; J encks, W. P. J . Am. Chem.
Soc. 1984, 106, 1361-1372.