1222 J. Am. Chem. Soc., Vol. 119, No. 6, 1997
Meng et al.
The high-performance liquid chromatography analyses were carried
out with a Hewlett-Packard 1090 liquid chromatograph equipped with
a diode-array detector on a C18 (5 µm, 3 × 100 mm) reversed-phase
column. The mobile phase was a solution of acetonitrile in water. The
reactions were studied at constant temperature in a HETO 01 PT 623
thermostat bath. The pH was measured using a Radiometer PHM82
pH meter with an Ingold micro glass electrode.
The GC analyses were carried out with a Varian 3400 capillary gas
chromatograph equipped with a flame ionization detector. Nitrogen
was used as the carrier gas. The column was a fused-silica capillary
column (Rescom, SE54, 25 m, 250 µm). The injection temperature
was 250 °C, and the column temperature was maintained constant at
200 °C.
group and nucleophile which has been seen previously in
nucleophilic displacement reactions.17 It is likely caused by a
favorable interaction between polarizable entering and leaving
groups in the “coupled” SN2 transition state.
The large assistance provided by efficient nucleophiles is in
strong contrast to the anomalously small nucleophilic discrimi-
nations which were observed for the corresponding tertiary
substrates. For example, the tertiary bromide reacts to give
substitution products only about three times more rapidly with
a thiocyanate anion than with a solvent water molecule.10 The
reactions of the tertiary substrates, owing to the very short
lifetime of the ion-pair intermediate, occur through stepwise
preassociation mechanisms.
Thiocyanate ion, owing to its ambident character, gives rise
to two products (Table 5). There is a change in reactivity of
the S and N parts of the nucleophile with a change in the leaving
group of the substrate. The more polarizable (“soft”) the leaving
group is the more of 1-SCN relative to 1-NCS is formed. This
is in accord with the concept of synergism between leaving
group and nucleophile which reflects favorable interaction
between polarizable entering and leaving groups in the coupled,
concerted transition state, since sulfur is more easily polarized
than nitrogen. Consistently, the Grunwald-Winstein parameter
mNCS is significantly greater than mSCN for reaction of 1-OBs,
which shows that the transition state with the N atom as
nucleophile is more polar than the transition state with the S
atom.2 Moreover, there is a gradual increase in the reactivity
of S relative to N of thiocyanate in the order 1-OBs < 2a-OBs
≈ 2b-OBs < 3-OBs (Table 5).
Materials. Merck silica gel 60 (240-400 mesh) was used for flash
chromatography. Diethyl ether and tetrahydrofuran were distilled under
nitrogen from sodium and benzophenone. Pyridine and methylene
chloride were distilled under nitrogen from calcium hydride. 2-Bro-
mofluorene was purchased from Lancaster and used without further
purification. Methanol and acetonitrile were of HPLC grade. All other
chemicals were of reagent grade and used without further purification.
The deuterium content of all the deuteriated compounds was measured
1
2
by H NMR to be >99.5 atom % H in the 9-position of the fluorene
moiety. The deuteriated compounds 2-bromo-(9-2H)-9-(1-X-ethyl)-
fluorene and 2,7-dibromo-(9-2H)-9-(1-X-ethyl)fluorene (X ) OH, Br,
I, OBs) were synthesized using the same methods as used for the
corresponding nondeuteriated analogs.
2-Bromo-(9,9-2H2)-fluorene and 2,7-Dibromo-(9,9-2H2)-fluorene
were prepared by the same method as has been used for synthesis of
(9,9-2H2)-fluorene.2,23
(R,R)- and (R,S)-2-Bromo-9-(1-hydroxyethyl)fluorene (2a-OH)
and (2b-OH). A solution of butyllithium (12.8 mL of a 1.6 M solution
in hexane, diluted with 30 mL of dry ether) was added to 2-bromof-
luorene (5 g), dissolved in dry ether (100 mL), at <-50 °C. After the
mixture was stirred at this temperature for 1.5 h, freshly distilled
acetaldehyde (30 mL) was added slowly with stirring. After addition,
the mixture was stirred for another 10 min. The reaction mixture was
poured into a mixture of ice and 2 M hydrochloric acid. The mixture
was extracted with ether three times. The combined ether fractions
were washed with water to neutrality, followed by washing with brine.
Recrystallization from pentane-ether and pentane-dichloromethane
gave pure diastereomer 2a-OH: mp 138-139 °C.
The mother liquid was recrystallized further to give a mixture of
the two diastereomers. These were separated with flash chromatography
on silica gel with hexane-ethyl acetate-dichloromethane (9:1:2) as
eluent. The end fractions contained pure 2b-OH: mp 107-108 °C.
(R,R)-2-Bromo-9-(1-bromoethyl)fluorene (2a-Br) was prepared by
treatment of the alcohol 2a-OH with ZnBr2-HBr in chloroform
according to the method described before.4 The reaction was followed
by HPLC. Recrystallization from methanol and hexane gave a product
with >99% diastereomeric purity. No other impurities were detected:
mp 97-99 °C. The same method was used to prepare (R,S)-2-Bromo-
9-(1-bromoethyl)fluorene (2b-Br) from 2b-OH: >98% diastereomeric
purity; mp 83-84 °C.
(R,R)-2-Bromo-9-(1-chloroethyl)fluorene (2a-Cl) was prepared
from the alcohol 2a-OH by reaction with ZnCl2-HCl in chloroform
as above. Isolation and recrystallization gave a product with >98%
diastereomeric purity: mp 73-74 °C. The same method was used to
prepare (R,S)-2-Bromo-9-(1-chloroethyl)fluorene (2b-Cl) from 2b-
OH: >96% diastereomeric purity; mp 87-88 °C.
(R,R)-2-Bromo-9-(1-iodoethyl)fluorene (2a-I) was prepared from
the alcohol 2a-OH by reaction with ZnI2-HI in chloroform as above.
Recrystallization several times from methanol and hexane gave the
product with >98% diastereomeric purity: mp 93-95 °C. Similarily,
(R,S)-2-Bromo-9-(1-iodoethyl)fluorene (2b-I) was prepared from the
alcohol 2b-OH. Recrystallization from hexane-benzene (1:1) gave a
product with >98% diastereomeric purity: mp 106-107 °C.
(R,R)-2-Bromo-9-(1-((4′-bromobenzenesulfonyl)oxy)ethyl)-
fluorene (2a-OBs) was synthesized by stirring a mixture of 2a-OH
An explanation is that the isocyanate product comes from
reaction through a stepwise preassociation carbocation mech-
anism but the thiocyanate originates from a coupled concerted
reaction. Another possibility is that both products are formed
by SN2 reactions but that there is a gradual change in the positive
charge on the central carbon atom. The fact that only 77-
78% inversion is observed with 2a-OBs and 2b-OBs supports
the first alternative. The nucleophilic selectivity kSCN/kHOH with
thiocyanate anion shows the same trend as the thiocyanate-
isocyanate product ratio from 16 with 1-OBs to 122 with 3-OBs
(Table 5).
The reactions with water in aqueous acetonitrile and aqueous
methanol show a surprisingly large amount of retention, about
90% (Table 4). A reasonable explanation is that π-orbitals of
the fluorenyl moiety assist the ionization by interaction with
the developing p-orbital on the backside of the reaction center.
Theoretical calculations by MNDO methods support this
conclusion.18 Thus, it has been reported that the fluorenylmethyl
carbocation is stabilized significantly by such interactions. The
somewhat smaller amount of retention with methanol as
nucleophile may indicate some contribution from an SN2
reaction route.
Experimental Section
General Procedures. NMR spectra were recorded with a Varian
XL 300 or a Unity 400 spectrometer for 1H at 300 MHz and 400 MHz,
for 13C at 75.4 MHz and 100.6 MHz, at 25 °C unless stated otherwise.
Chemical shifts are indirectly referenced to TMS via the solvent signal
(chloroform-d1 7.26 and 77.00 ppm; DMSO-d6 2.49 and 39.5 ppm).
NMR signals were assigned from P.E.COSY,19 HSQC,20 HSBC,21 and
NOE difference spectra.22
(17) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383-
1396.
(18) Ohwada, T. J. Am. Chem. Soc. 1992, 114, 8818-8827.
(19) Mueller, L. J. Magn. Reson. 1987, 72, 191-196.
(20) (a) Bodenhausen, G.; Ruben, D. Chem. Phys. Lett. 1980, 69, 185-
189. (b) Torres, A. M.; Nakashima, T. T.; McClung, R. E. D. J. Magn.
Reson. 1993, A102, 219-227.
(21) Ko¨ve´r, K. E.; Prakash, O.; Hruby, V. Magn. Reson. Chem. 1993,
31, 231-237.
(22) Sanders, J. K. M.; Mersh, J. D. in Prog. Nucl. Magn. Reson.
Spectrosc.; Emsley, J. W., Feeney, J., Sutcliffe, L. H., Eds.; Pergamon
Press: Oxford, 1982; Vol. 15, p 353-400.
(23) Ek, M. Abstracts Uppsala Dissertations from the Faculty of Sciences,
692; Acta Universitatis Upsaliensis, Sweden, 1983.