Aminocyclodextrins to facilitate the deprotonation of 4-tert-butyl-α- nitrotoluene

Article abstract of DOI:10.1039/b506187c

6^A-Amino-6^A-deoxy-β-cyclodextrin enhances the rate of the deprotonation of 4-terf-butyl-α-nitrotoluene. The rate constants for reaction of the cyclodextrin-bound species, k_inc = 4 × 10^-3, 9 × 10^-3 and

Full text of DOI:10.1039/b506187c

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A R T I C L E
Aminocyclodextrins to facilitate the deprotonation of
4-tert-butyl-a-nitrotoluene
Lorna Barr,a Christopher J. Easton,*a Kitty Leea and Stephen F. Lincolnb
a Research School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra, ACT 0200, Australia. E-mail: easton@rsc.anu.edu.au
b School of Chemistry and Physics, University of Adelaide, Adelaide, SA 5005, Australia
Received 4th May 2005, Accepted 6th June 2005
First published as an Advance Article on the web 18th July 2005
6A-Amino-6A-deoxy-b-cyclodextrin enhances the rate of the deprotonation of 4-tert-butyl-a-nitrotoluene. The rate
constants for reaction of the cyclodextrin-bound species, kinc = 4 × 10−3, 9 × 10−3 and 19 × 10−3 s−1, at pH 6.0, 6.5
and 7.0, respectively, in 0.1 mol dm−3 aqueous phosphate buffer containing 1% methanol at 298 K. These rate
constants correspond to a rate acceleration (kinc/kun) of ca. 10 times at each pH. Under the same conditions,
6A-dimethylamino-6A-deoxy-b-cyclodextrin and 6A-(2-aminoethylamino)-6A-deoxy-b-cyclodextrin are more effective;
at pH 6.0, 6.5 and 7.0, for the former, kinc = 3 × 10−2, 7 × 10−2 and 12 × 10−2 s−1, whilst for the latter, kinc = 4 × 10−2,
5 × 10−2 and 9 × 10−2 s−1, respectively. Each cyclodextrin also decreases the pKa of the nitrotoluene, from 6.8 in free
solution, to 6.2 when bound. The accelerated deprotonation by 6A-amino-6A-deoxy-b-cyclodextrin is reflected in the
enhanced rates of hydrogen–deuterium exchange of the nitrotoluene in deuterium oxide, and in the conjugate
addition of the nitrotoluene to methyl vinyl ketone in aqueous solution.
nitronate 3 had kmax 300 nm (e 22,000 mol−1 dm3 cm−1), at which
Introduction
wavelength the nitroalkane 2 displayed negligible absorption.
Natural and modified cyclodextrins have been studied ex-
At pH 6.0, 6.5 and 7.0, in 0.1 mol dm−3 aqueous phosphate
tensively as catalysts and enzyme mimics.1 The modified
cyclodextrins have incorporated a wide range of functional
buffer containing 1% methanol at 298 K, the nitrotoluene 2
deprotonated with pseudo-first order rate constants of 4 ×
10−4, 9 × 10−4 and 15 × 10−4 s−1, respectively. The modified
cyclodextrins 1a–c were prepared as reported.11,12 The pKa of the
protonated dimethylaminocyclodextrin 1b was measured to be
8.6, while those of the conjugate acids of the aminocyclodextrin
1a and the aminoethylaminocyclodextrin 1c have been reported
as 8.9, and 5.7 and 9.4, respectively.11
groups, including a variety of basic residues.2,3 For exam-
ple, Breslow et al.3 have shown that imidazole-substituted
cyclodextrins can be exploited as either acid or base cata-
lysts, and in particular cases they have used bisimidazole-
substituted cyclodextrins for concerted acid–base catalysis. The
objective of the present work was to explore the effects of
the simple amino-substituted cyclodextrins 6A-amino-6A-deoxy-
b-cyclodextrin (1a), 6A-dimethylamino-6A-deoxy-b-cyclodextrin
(1b) and 6A-(2-aminoethylamino)-6A-deoxy-b-cyclodextrin (1c)
on the deprotonation of 4-tert-butyl-a-nitrotoluene (2). Ni-
troalkanes, such as this deprotonate under neutral or mildly
basic conditions,4 and the product nitronates are versatile
intermediates in organic synthesis;5,6 they undergo nitroaldol
(Henry) reactions with aldehydes and ketones,7 and Michael
additions with electron-deficient olefins.6,8 However, the rates of
deprotonation of nitroalkanes are anomalously slow for acid–
base reactions.9 For example, the half-life for reaction of the
nitrotoluene 2 at pH 7.0 and 298 K is ca. 8 min, so this process
is an obvious target for rate enhancement.
The complexation of the nitrotoluene 2 by b-cyclodextrin and
1
the modified cyclodextrins 1a–c was studied using H NMR
spectroscopy, at 298 K in deuterium oxide containing 1% d4-
methanol and 0.1 mol dm−3 phosphate buffer, adjusted to pD
4.4, 8.4 and 11.4 with either sodium deuteroxide or deuterium
chloride. These pD values were chosen to encompass the various
stages of protonation and deprotonation of the cyclodextrins 1a–
c and the nitrotoluene 2 in aqueous solutions, based on the pKa
values described above. The samples contained 0.2 mmol dm−3
of the nitrotoluene 2 and ranged in cyclodextrin concentration
from 0.0–1.5 mmol dm−3. With each cyclodextrin and at each
pD, the chemical shift due to the signal of the tert-butyl group of
the nitrotoluene 2 moved downfield with increasing cyclodextrin
concentration (Fig. 1). Curve fitting of these data showed that
the association constants (eqn. 1) of the host–guest complexes
of the nitrotoluene 2 with b-cyclodextrin and the modified
cyclodextrins 1a–c are greater than 10000 dm3 mol−1, irrespective
of the charged state of either the nitrotoluene 2 or the hosts. It
is reasonable to expect that the corresponding values in water
would be similar and, on the basis of that and eqn. 1, to assume
that the nitrotoluene 2 is effectively, completely complexed in
aqueous solutions containing 0.1 mmol dm−3 of the nitrotoluene
2 and at least 10 mmol dm−3 of either b-cyclodextrin or one of
the modified cyclodextrins 1a–c. These conditions were therefore
used to measure the extents and rates of deprotonation of the
nitrotoluene 2 in the host–guest complexes.
Results and discussion
The nitrotoluene 2 was chosen as the substrate because it was
expected to readily include into the cavity of the modified
cyclodextrins 1a–c. It was also expected to deprotonate at near
neutral pH to give the chromophoric nitronate anion 3. In
the event, it was prepared by treatment of the corresponding
bromide with silver nitrite,10 and found to have a pKa of 6.8. The
K (dm3 mol−1) = [complex]/[host]·[guest]
(1)
Accordingly, pKas of 6.7, 6.2, 6.2 and 6.2 were measured for
the nitrotoluene 2 included in the annulus of b-cyclodextrin and
2 9 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 0 – 2 9 9 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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nitrotoluene 2 and the cyclodextrins 1a–c, to decrease the
guest pKa, reflects the ability of the cyclodextrins’ protonated
amino groups to form ion-pairs with, and therefore stabilise, the
included nitronate 3.
The pKa of the nitrotoluene 2 reflects the ratio of the rate of its
deprotonation and the rate of protonation of the corresponding
nitronate 3. Since each of the cyclodextrins 1a–c reduces this
pKa by 0.6, it follows that the ratio is altered by a factor of
approximately 4. Given that the cyclodextrins 1a–c increase the
rate of deprotonation by factors ranging from 10–100, they must
also increase the rate of protonation of the nitronate 3 by 2–
25 times. It seems likely that this effect is due to the proximity of
the cyclodextrins’ protonated amino groups to deliver a proton
to the nitronate 3.
Based on the observations above, the cyclodextrins 1a–c
should increase the rate of deuteration of the nitrotoluene
2 in deuterium oxide. To investigate this, solutions of the
nitrotoluene 2 (1 mmol dm−3) with either b-cyclodextrin or
the aminocyclodextrin 1a (5 mmol dm−3), in deuterium oxide
containing 10% d4-methanol and 0.1 mol dm−3 phosphate
Fig. 1 The change in chemical shift of the signals due to the tert-butyl
group of 2 (0.2 mmol dm−3) plotted as a function of increasing cyclodex-
trin concentration for 6A-dimethylamino-6A-deoxy-b-cyclodextrin (1b)
(0.0–1.5 mmol dm−3) in 0.1 mol dm−3 phosphate buffer, at pD 4.4,
containing 1% d4-methanol at 298 K.
1
buffer, at 298 K and pD 6.4, were monitored using H NMR
spectroscopy. Under these conditions, the pseudo-first order
rate constants for hydrogen–deuterium exchange of the acidic
methylene protons of the nitrotoluene 2 were observed to be
1.0 × 10−4 s−1 with b-cyclodextrin and 23 × 10−4 s−1 with the
amine 1a. It was not practical to examine the reaction in the
absence of a cyclodextrin, due to the limited aqueous solubility
of the nitrotoluene 2 unless complexed.
The utility of the cyclodextrins 1a–c increasing the rate
and extent of deprotonation of the nitroalkane 2 depends
on the nitronate 3 being accessible for further reactions. To
examine this, reaction of the nitronate 3 with methyl vinyl
ketone (4) to give the adduct 5 was investigated (Scheme 1).
Mixtures of the nitrotoluene 2 (5 mmol dm−3) and methyl
vinyl ketone (5 mmol dm−3), and either b-cyclodextrin or the
aminocyclodextrin 1a (25 mmol dm−3), in 0.1 mol dm−3 pH 6.0
aqueous phosphate buffer containing 1% methanol, were left
stirring at 298 K. Again, it was not possible to examine the
reaction in the absence of a cyclodextrin due to the low aqueous
solubility of the nitrotoluene 2. Under these conditions, after
24 h the yield of the adduct 5 was 68% when the reaction was
carried out in the presence of the aminocyclodextrin 1a, but
only small quantities (<10%) were recovered from the mixture
containing b-cyclodextrin.
the modified cyclodextrins 1a–c, respectively. At pH 6.0, 6.5 and
7.0, in 0.1 mol dm−3 aqueous phosphate buffer containing 1%
methanol at 298 K, the pseudo-first order rate constants for
deprotonation of the nitrotoluene 2 included in the cavity of
b-cyclodextrin (kinc) were found to be 3 × 10−4, 8 × 10−4 and
14 × 10−4 s−1, respectively, while the corresponding values for
the modified cyclodextrins 1a–c were 4 × 10−3, 9 × 10−3 and 19 ×
10−3 s−1, 3 × 10−2, 7 × 10−2 and 12 × 10−2 s−1, and 4 × 10−2, 5 ×
10−2 and 9 × 10−2 s−1. Very similar rate constants were obtained
when either higher or lower cyclodextrin concentrations were
used, confirming the expectation that the nitrotoluene 2 is
fully complexed and that the measurements reflect the rates of
deprotonation of the complexed species. When ethanolamine
was used instead of a cyclodextrin, the pKa of the nitrotoluene
2 was 6.9 and the observed pseudo-first order rate constants for
deprotonation of the nitrotoluene 2 (kobs) at pH 6.0, 6.5 and 7.0
were 4 × 10−4, 9 × 10−4 and 15 × 10−4 s−1, respectively.
Neither b-cyclodextrin nor ethanolamine increases the rate
of deprotonation of the nitrotoluene 2. By comparison, the
aminocyclodextrin 1a accelerates the rate of deprotonation by
approximately 10 times at each pH studied. The deprotonation
rate increases with increasing pH, presumably because the active
form of the cyclodextrin 1a is the free base and, since the
pKa of the protonated form of the cyclodextrin 1a is 8.9, the
concentration of the base also increases when going from pH 6.0
to 7.0. The dimethylaminocyclodextrin 1b is more effective,
increasing the rate of deprotonation of the nitrotoluene 2 by
approximately 75 times at each pH studied. The greater effect of
this cyclodextrin is probably due, at least in part, to its lower pKa
value, and the consequently higher concentration of the free base
form at pH 6.0–7.0. The ethylenediamine 1c is also more efficient
than the aminocyclodextrin 1a, but the rate of deprotonation by
this species does not show the same increase with increasing pH
as observed with the aminocyclodextrins 1a and 1b. In this case
it is likely that both the monoprotonated and the free base form
of the cyclodextrin 1c promote reaction, and the pH dependence
on the rate of deprotonation of the nitrotoluene 2 reflects the
concentrations of these species.
The extent of deprotonation of the nitrotoluene 2 at equi-
librium at a given pH, as reflected in the pKa, is little affected
by either b-cyclodextrin or ethanolamine. However, each of the
modified cyclodextrins 1a–c increases the extent of deprotona-
tion and reduces the pKa by approximately 0.6. The pKas of other
acids, such as benzoic acids, are known to be altered on inclusion
in cyclodextrins.13 In those cases the effect is attributable to
inclusion of uncharged, more hydrophobic species in preference
to the corresponding anions. As a consequence the pKas are
increased. Presumably, the peculiar effect observed with the
Scheme 1
In summary, this work demonstrates that an aminocyclodex-
trin can increase both the rate and extent of deprotonation
of a nitroalkane without interfering with the reactions of the
resultant nitronate. In the formal sense, the cyclodextrins are
thus behaving as catalysts, since they exert their effects without
being altered, but in a practical sense they are only effective
when used in excess rather than catalytic amounts. In addition
to the effects on deprotonation, this work shows the advantage
of using cyclodextrins to increase the aqueous solubility of
organic compounds, facilitating the use of this solvent for
chemical transformations. The more general application of these
results will depend on the identification of alternative molecular
hosts that are compatible with a wide range of nitroalkanes,
but the basic principles of this form of catalysis have been
established.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 0 – 2 9 9 3
2 9 9 1

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Table 1 Association constants K of the complexes formed between
4-tert-butyl-a-nitrotoluene (2) and either b-cyclodextrin or one of the
aminocyclodextrins 1a–c in 0.1 mol dm−3 phosphate buffer, at pD 11.4
(A), 8.4 (B) and 4.4 (C), containing 1% d4-methanol at 298 K
Experimental
General
1H and 13C NMR spectra were recorded on Varian Gemini
300 and Varian Inova 500 spectrometers. Electron impact mass
spectra were recorded on a Micromass VG AutoSpec mass
spectrometer, operating with an ionisation potential of 70 eV.
UV spectra were recorded using a Shimadzu UV-2101PC UV-
vis scanning spectrophotometer coupled to a Shimadzu CPS
temperature controller or a stopped-flow spectrometer (Model
SF. 17MV). The Australian National University Microanalytical
Service performed the elemental analyses. Melting points were
determined on a Kofler hot-stage melting point apparatus under
a Reichert microscope.
K ×10−4/dm3 mol−1
Cyclodextrin
A
B
C
b-Cyclodextrin
2.6 0.6
2.0 0.3
3.0 0.8
2.9 0.4
1.2 0.3
2.0 0.2
4.6 0.8
4.1 0.6
4.4 0.9
1.1 0.1
2.2 0.3
1.0 0.1
1a
1b
1c
Determination of the pKa of the nitrotoluene 2 alone and in the
presence of either ethanolamine, b-cyclodextrin or one of the
aminocyclodextrins 1a–c
4-tert-Butylbenzyl bromide and methyl vinyl ketone (4) were
purchased from Sigma-Aldrich Chemical Co. b-Cyclodextrin
was the generous gift of Nihon Shokuhin Kako Co. It was
recrystallised from water and dried in vacuo over P2O5 to
constant weight before use. The modified cyclodextrins 1a–c
were prepared as previously reported.11,12 Water was deionised
and then purified with a Milli-QTM reagent system to ensure
a resistivity of <15 MX cm. Phosphate buffer solutions were
Solutions of the nitrotoluene 2 (0.1 mmol dm−3), alone or in
the presence of either ethanolamine, b-cyclodextrin or one of
the aminocyclodextrins 1a–c (10.0 mmol dm−3), were made
up in aqueous phosphate buffer (0.1 mol dm−3) containing
1% d4-methanol, and adjusted to the chosen pH values using
either NaOH–H2O or NaH2PO4–H2O. Their UV spectra were
then recorded at 298 K. At high pH values, the spectra of
the solutions are attributable to the nitronate 3, which was
therefore determined to have a kmax at 300 nm, with e =
22,000 mol−1 dm3 cm−1. At low pH values the spectra of
the solutions, which then contain the nitrotoluene 2, showed
negligible absorbance at this wavelength. At high and low
pH values, the spectra are not significantly affected by either
ethanolamine or any of the cyclodextrins. The absorbance of
the solutions at 300 nm was recorded and plotted as a function
of pH (Fig. 2). From these curves, pKa values were determined,
from the pH at which the absorbance at 300 nm was half that of a
solution of high pH. On this basis, the pKa of the nitrotoluene 2,
alone and in the presence of either ethanolamine, b-cyclodextrin
or one of the aminocyclodextrins 1a–c, was determined to be
6.8 0.1, 6.9 0.1, 6.7 0.1, 6.2 0.1, 6.2 0.1 and 6.2
0.1, respectively.
R
prepared using an Orion PerpHecTꢀ Meter, Model 320. The
pKa of the protonated dimethylaminocyclodextrin 1b was mea-
sured to be 8.6, using the procedure reported previously for
determination of the pKas of the aminocyclodextrin 1a and the
aminoethylaminocyclodextrin 1c.11
4-tert-Butyl-a-nitrotoluene (2)
4-tert-Butylbenzyl bromide (11.4 g, 50 mmol) was added drop-
wise over 1 h to a slurry of AgNO2 (10.0 g, 65 mmol) and
CaH2 (0.1 g, 2.4 mmol) in diethyl ether (60 cm3) maintained at
◦
◦
0 C. The mixture was stirred for a further 26 h at 0 C, after
which it was filtered and the filter cake washed with diethyl ether
(3 × 50 cm3). The combined filtrates were concentrated under
reduced pressure to give a crude oil comprising the nitrotoluene 2
and the related nitrite ester in a ratio of 43 : 57. Chromatography
of the oil on silica gel, eluting with ethyl acetate–hexane (1 : 9,
v : v), gave the nitrotoluene 2 as a colourless crystalline solid
(3.4 g, 35%): mp 27–28 ◦C; (Found: C, 68.67; H, 7.54; N, 7.00%.
C11H15NO2 requires C, 68.37; H, 7.82; N, 7.25%); dH (300 MHz,
CDCl3) 7.45 (d, 2H, J 8.7), 7.39 (d, 2H, J 8.7), 5.42 (s, 2H), 1.33
(s, 9H); dC (75 MHz, CDCl3) 153.1, 129.6, 126.7, 126.0, 79.8,
•
34.8, 31.3; m/z (EI) 193 (0.3%, M+ ), 178 (3), 147 (100), 132 (51)
and 91 (55).
Determination of the association constants, K, of the complexes
of the nitrotoluene 2 with b-cyclodextrin and the
aminocyclodextrins 1a–c in D2O at pD 4.4, 8.4 and 11.4
Solutions of the nitrotoluene 2 (0.2 mmol dm−3) and either b-
cyclodextrin or one of the aminocyclodextrins 1a–c (0–7.5 mol.
equiv.) in phosphate buffer (0.1 mol dm−3) were made up in
D2O containing 1% d4-methanol, and adjusted to pD 4.4, 8.4
or 11.4 with either NaOD–D2O or DCl–D2O. They were then
analysed at 298 K using 1H NMR spectroscopy (500 MHz). The
changes in the chemical shift of the resonance due to the tert-
butyl protons of the nitrotoluene 2 were recorded and plotted
as a function of cyclodextrin concentration (Fig. 1), and curves
were fitted to the data according to eqn. 1 and 2 by applying non-
Fig. 2 Relative absorbance, at 300 nm plotted as a function of pH, for
series of solutions of the nitroalkane 2 (0.1 mmol dm−3) at different pH
values, in 0.1 mol dm−3 phosphate containing 1% methanol at 298 K, in
the presence and in the absence of the amine 1a (10 mmol dm−3).
Determination of the pseudo-first order rate constants for
deprotonation of the nitrotoluene 2 in aqueous solution, alone
and in the presence of either ethanolamine, b-cyclodextrin or one
of the aminocyclodextrins 1a–c, at pH 6.0, 6.5 and 7.0
R
linear regression analysis using Mac-Curvefit v1.2ꢀ. This gave
the values for the association constants, K, that are summarised
in Table 1.
Solutions of the nitrotoluene 2 (0.1 mmol dm−3), alone and in
the presence of either ethanolamine, b-cyclodextrin or one of
the aminocyclodextrins 1a–c (10.0 mmol dm−3), were made up
in aqueous phosphate buffer (0.1 mol dm−3) containing 1% d4-
methanol, and adjusted to either pH 6.0, 6.5 or 7.0 using either
NaOH–H2O or NaH2PO4–H2O. Their absorbance was then
[guest] · dfree + [complex] · dcomplexed
dobserved
=
(2)
[guest] + [complex]
2 9 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 0 – 2 9 9 3

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evident in the 1H NMR spectrum of the crude product mixture.
Based on the ratio of the nitrotoluene 2 to the adduct 5, the yield
was determined to be <10%.
Table 2 Pseudo-first order rate constants for the deprotonation of the
nitrotoluene 2 (0.1 mmol dm−3), at pH 6.0, 6.5 and 7.0, in 0.1 mol dm−3
phosphate buffer containing 1% methanol at 298 K, alone and in
the presence of either ethanolamine, b-cyclodextrin or one of the
aminocyclodextrins 1a–c (10 mmol dm−3
)
Acknowledgements
kobs ×102/s−1
The authors acknowledge the assistance of Dr N. Brasch with
the stopped-flow UV spectrophotometric experiments, and the
financial support provided by the Australian Research Council
for this work.
pH kun ×102/s−1 Ethanolamine b-Cyclodextrin 1a 1b 1c
6.0 0.04
6.5 0.09
7.0 0.15
0.04
0.09
0.15
0.03
0.08
0.14
0.4
0.9
1.9 12
3
7
4
5
9
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recorded as a function of time at 298 K, using either conventional
or stopped-flow UV spectrophotometry, at 300 and 325 nm,
respectively, to monitor appearance of the nitronate 3. The rates
of deprotonation of the nitrotoluene 2 determined in this manner
from the initial rates of reaction are summarised in Table 2. These
values are the average of at least three determinations, and the
results of individual experiments varied by less than 10%.
3-(4-tert-Butylphenyl)-3-nitropropyl methyl ketone (5)
Method 1. A solution of diisopropylamine (10 mg, 0.1 mmol),
methyl vinyl ketone (4) (73 mg, 1.0 mmol) and 4-tert-butyl-a-
nitrotoluene (2) (200 mg, 1.0 mmol) in acetonitrile (1 cm3) was
stirred at 298 K for 24 h, before being poured into aqueous
HCl (0.1 mol dm−3, 5 cm3). The aqueous solution was extracted
with diethyl ether (3 × 15 cm3), and the combined organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue on silica, eluting with
ethyl acetate–hexane (1 : 9, v : v) afforded 3-(4-tert-butylphenyl)-
3-nitropropyl methyl ketone (5) as a colourless solid (120 mg,
46%): mp 61–62 ◦C; (Found: C, 68.13; H, 8.12; N, 5.06%.
C15H21NO3 requires C, 68.42; H, 8.04; N, 5.32%); dH (300 MHz,
CDCl3) 7.42 (d, 2H, J 8.7), 7.37 (d, 2H, J 8.7), 5.51 (dd, 1H,
J 9.1, J 5.8), 2.68 (m, 1H), 2.50 (t, 2H, J 7.0), 2.38 (m, 1H),
2.14 (s, 3H), 1.31 (s, 9H); dC (75 MHz, CDCl3) 206.1, 153.0,
131.0, 127.3, 125.9, 89.9, 39.3, 34.8, 31.3, 30.1, 27.6; m/z (EI)
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Downey, J. Am. Chem. Soc., 2003, 125, 12692.
•
263 (0.01%, M+ ), 248 (25), 233 (52), 217 (82), 143 (84) and 57
(100).
Method 2. Methyl vinyl ketone (4) (35 mg, 0.50 mmol),
4-tert-butyl-a-nitrotoluene (2) (10 mg, 0.052 mmol) and 6A-
amino-6A-deoxy-b-cyclodextrin (1a) (285 mg, 0.25 mmol) were
dissolved in phosphate buffer (pH 6.0, 0.1 mol dm−3, 10 cm3)
containing 1% methanol, and the mixture was stirred at 298 K
for 24 h, before being poured into aqueous HCl (0.1 mol dm−3,
5 cm3). The aqueous solution was extracted with diethyl ether
(3 × 15 cm3), and the combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Chromatog-
raphy of the residue on silica, eluting with ethyl acetate–hexane
(1 : 9, v : v), afforded 3-(4-tert-butylphenyl)-3-nitropropyl methyl
ketone (5) as a colourless solid (9.3 mg, 68%).
8 (a) R. Ballini, P. Marziali and A. Mozzicafreddo, J. Org. Chem.,
1996, 61, 3209; (b) N. Halland, R. G. Hazell and K. A. Jørgensen,
J. Org. Chem., 2002, 67, 8331; (c) N. Ono, A. Kamimura, H. Miyake,
I. Hamamoto and A. Kaji, J. Org. Chem., 1985, 50, 3692.
9 (a) F. G. Bordwell and W. J. Boyle, Jr., J. Am. Chem. Soc., 1972, 94,
3907; (b) A. J. Kresge, Can. J. Chem., 1974, 52, 1897.
10 N. Kornblum, R. A. Smiley, R. K. Blackwood and D. C. Iffland,
J. Am. Chem. Soc., 1955, 77, 6269.
11 B. L. May, S. D. Kean, C. J. Easton and S. F. Lincoln, J. Chem. Soc.,
Perkin Trans. 1, 1997, 3157.
12 K. Hamasaki, H. Ikeda, A. Nakamura, A. Ueno, F. Toda, I. Suzuki
and T. Osa, J. Am. Chem. Soc., 1993, 115, 5035.
13 (a) K. A. Connors and J. M. Lipari, J. Pharm. Sci., 1976, 65, 379;
(b) K. A. Connors and T. W. Rosanske, J. Pharm. Sci., 1980, 69, 173;
(c) T. Aoyagi, A. Nakamura, H. Ikeda, T. Ikeda, H. Mihara and A.
Ueno, Anal. Chem., 1997, 69, 659.
When the reaction was repeated using b-cyclodextrin instead
of the aminocyclodextrin 1a, only traces of the adduct 5 were
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 0 – 2 9 9 3
2 9 9 3