New biphenylic derivatives: Synthesis, characterisation and enantiodiscrimination in chiral aggregates

Article abstract of DOI:10.1016/j.tetasy.2004.01.038

Chiral discrimination of racemic 2,2′-diamino-6-(octanoyloxymethyl) biphenyl and 2,3′-diamino-6-(octanoyloxymethyl)biphenyl in micelles formed either by N-alkyl-N,N-dimethyl-N-(S)-(1-phenyl)ethylammonium bromide or sodium N-dodecanoyl-L-prolinate has been

Full text of DOI:10.1016/j.tetasy.2004.01.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 987–994
New biphenylic derivatives: synthesis, characterisation and
enantiodiscrimination in chiral aggregates
Romana Andreani,a Cecilia Bombelli,a Stefano Borocci,b Juri Lah,c Giovanna Mancini,d,*
Paolo Mencarelli,a Gorazd Vesnaverc and Claudio Villanie
aDip. di Chimica Universitꢀa degli Studi di Roma ‘La Sapienza’, P.le A. Moro 5, 00185 Roma, Italy
bDipartimento di Scienze Ambientali, Universitꢀa della Tuscia, Largo dell’ Universitꢀa, 01100 Viterbo, Italy
cDepartment of Chemistry, University of Ljiubljana, Aꢁskerꢁceva 5, 1000 Ljubljana, Slovenia
dCNR Istituto di Metodologie Chimiche Sezione Meccanismi di Reazione c/o dip. Chimica Universitꢀa degli Studi di Roma
‘La Sapienza’, P.le A. Moro 5, 00185 Roma, Italy
eDip. di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive Universitꢀa degli Studi di Roma ‘La Sapienza’,
P.le A. Moro 5, 00185 Roma, Italy
Received 15 December 2003; accepted 28 January 2004
Abstract—Chiral discrimination of racemic 2,20-diamino-6-(octanoyloxymethyl)biphenyl and 2,30-diamino-6-(octanoyloxy-
methyl)biphenyl in micelles formed either by N-alkyl-N,N-dimethyl-N-(S)-(1-phenyl)ethylammonium bromide or sodium
N-dodecanoyl-L
-prolinate has been investigated by 1H NMR spectroscopy. The rotational barrier of 2,30-diamino-6-(octanoyl-
oxymethyl)biphenyl has been evaluated by HPLC and by dynamic NMR. The rotational barrier of 2,30-diamino-6-(acetoxy-
methyl)biphenyl was evaluated by theoretical calculations and compared with the experimental data relative to its analogue.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
preferential interactions of one of the enantiomers with
chiral aggregates may be revealed by a deracemisation
process. Moreover, the racemic mixture of some of these
atropoisomeric compounds is more accessible than
enantiopure molecules.
The study of chiral recognition in micellar aggregates is
of interest in many research fields. Micelles are in fact
very simple models of biomembranes and the identifi-
cation of non-covalent interactions responsible for chi-
ral recognition in these aggregates may be of help in
clarifying some of the recognition phenomena respon-
sible for membrane organisation. These same interac-
tions might also have played some role in the
homochirality of biomolecules either in the breaking of
symmetry1 or in the amplification of a first enantiomeric
imbalance.2 The increasing demand of enantiopure
molecules3 stimulates, besides enantioselective synthesis,
new methods both for enantioseparation and for enan-
tiopurity determination. The knowledge of the non-
covalent interactions responsible for chiral recognition
could address the preparation of new chiral selective
molecules. The use of atropoisomeric compounds
characterised by a relatively low rotational barrier is
very useful in this kind of investigation4 because the
1
Herein we report an H NMR investigation carried out
in aqueous solution of racemic 2,20-diamino-6-(octa-
noyloxymethyl)biphenyl 1a and 2,30-diamino-6-(octa-
noyloxymethyl)biphenyl 2a in the presence of aggregates
formed either by an anionic surfactant, sodium
N-dodecanoyl-L-prolinate 3, or cationic surfactants
N-alkyl-N,N-dimethyl-N-(S)-(1-phenyl)ethylammonium
bromide 4 (alkyl ¼ C12, 4a; alkyl ¼ C16, 4b). We also
report the evaluation of the rotational barrier of 2,30-
diamino-6-(octanoyloxymethyl)biphenyl 2a by dynamic
NMR experiments carried out in the presence of chiral
aggregates and by dynamic HPLC on a chiral phase.
The rotational barrier of a simpler analogue of the
biphenylic derivative 2a, namely 2,30-diamino-6-(acet-
oxymethyl)biphenyl 2b, was evaluated by theoretical
calculation.
The anionic chiral surfactant 3 has been studied exten-
sively in our laboratory and has been shown to be
* Corresponding author. Tel.: +39-0649913078; fax: +39-06490421;
e-mail: gmancini@uniroma1.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.038

988
R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
characterised by a high extent of organisation5 and to be
able to discriminate the enantiomers of biarylic deriva-
tives.6 Cationic surfactants 4 have been used as media
for diastereoselective reactions7 but, to the best of our
knowledge, have not been investigated in the
deracemisation of atropoisomeric compounds. Their
advantages are both the presence of an aromatic ring,
that could give p-stacking interactions with the solute,
and the commercial availability of both the enantiomers
of N,N-dimethyl-a-methylbenzylamine, which upon
alkylation yield the cationic surfactants 4. The possi-
bility of an easy preparation of both enantiomers of a
chiral surfactant is in fact an important point in this
kind of investigations.
the alkyl chains that accompanies the micellisation
process. Similarly, the more positive TDSMo contribution
observed with 4a can be ascribed to the larger amount of
hydrophobically structured water released upon micel-
lisation. The more favourable (exothermic) DHMo con-
tribution can be attributed to the higher number of van
der Waals contacts formed during the aggregation of the
longer chains of 4a. All thermodynamic parameters
determined for 4b and 4a agree well with the corres-
ponding values of cmc, DGoM, DHMo and TDSMo for
alkylpyridinium bromides and alkyltrimethylammo-
nium bromides of the same chain length.15;19
The biphenylic derivatives were prepared by Ulmann
coupling of 2-bromo-3-nitromethylbenzoate with
1-iodo-2-nitrobenzene or 1-iodo-3-nitrobenzene (for the
preparation of compounds 1a and 2a, respectively).
CH2OCOR
CH2OCOR
5
3
5
3
6'
5'
4'
3'
6'
5'
4'
4
4
The enantiomers of the two biphenylic derivatives were
resolved by HPLC on an amylose carbamate chiral
stationary phase. In the case of compound 1a, two well
resolved peaks were observed in the chromatograms at
temperatures in the range 298–318 K; evidence of a
stability towards enantiomer interconversion that al-
lowed us to characterise one of the enantiomers by CD
spectroscopy (Fig. 1).
2'
NH2
NH2
H2N NH2
2a, R=C7H15
2b, R=CH3
1a, R=C7H15
1b, R=CH3
CH3
CH3
Br
COO-Na+
H
N
CH3
H
N
3
R
The absence of peak broadening or plateau-like regions
(see further) in the chromatograms of 1a is consistent
with slow R/S-enantiomerisation on the time scale of the
HPLC separation, as expected for a tri-ortho substituted
biphenyl with medium sized substituents.11
O
C12H25
4a, R=C16H33
4b, R=C12H25
Under the same HPLC conditions, compound 2a yield-
ed a single peak at temperatures near or above 298 K.
When the column temperature was lowered in 5 K steps,
the peak progressively broadened and eventually split
into two peaks with a plateau-like region between them
at a column temperature of 268 K (Fig. 2). This
behaviour is consistent with enantiomer interconversion
becoming increasingly slower on the HPLC time scale.
2. Results and discussion
The chiral surfactants were prepared and purified
according to described procedures5;8 and then fully
characterised as reported in the experimental section.
The Krafft point9 and cmc10 of surfactants 4 were
measured according to reported procedures. Isothermal
titration microcalorimetry (ITC) experiments, carried
out for the measurement of the cmcs also yielded the
thermodynamic parameters of the micellisation of 4a
and 4b (Table 1), derived on the basis of the mass action
model of the micellisation process.10a;c;d
Computer simulation of the exchange-broadened elu-
tion profile obtained at 268 K (Fig. 2), gave the averaged
From Table 1 it is evident that micellisation of both
surfactants is an entropy driven process in which high
entropy contributions (T DSMo ) can be attributed to the
release of the hydrophobically structured water around
Table 1. Thermodynamic parametersa of micellisation for 4a and 4b at
398 K obtained from isothermal titration microcalorimetry10a
b
Surfactant cmc,
mmol kgꢀ1
DGoM
,
DHMo
,
TDSMo
,
kJ molꢀ1
kJ molꢀ1
kJ molꢀ1
4a
4b
0.24
7.7
)55.1
)39.6
)8.7
)3.1
46.4
36.5
a The relative errors in DGMo , DHMo and TDSMo (DHMo ꢀ DGoM) are esti-
mated to be about 2%, 10% and 2%, respectively.
b DGoM values were calculated using p=n ¼ 0.2, which is a characteristic
value for C12 and C16 analogue alkylpyridinium bromides.10e
Figure 1. CD spectrum of biphenylic derivative 1a in EtOH.

R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
989
All the calculations were carried out by using the
Gaussian 98 package.16 The DFT approach was used
with the Beckeꢀs three-parameter functional and with the
correlation functional of Lee, Yang and Parr (B3LYP).
In order to verify the effect of the basis set, the calcu-
lations were carried out at two levels of theory: at first,
the 6-31G(d) basis set (a split valence basis set supple-
mented with polarisation d-functions on heavy atoms)
was used and subsequently all the stationary points
found, were reoptimised with the 6-311+G(d,p) basis
set, a triple zeta basis set, plus diffuse functions added to
heavy atoms and with polarisation p-functions on
hydrogen and 2-d functions on heavy atoms. The
ground state structures and transition states for the
enantiomerisation of 2b were fully optimised, with each
stationary point found characterised by a frequency
calculation. For the structures featuring one imaginary
frequency and therefore found to be a saddle point, the
normal mode corresponding to the imaginary frequency,
was animated by using the Molden visualisation
programme.17 In this way it was verified that the dis-
placements that compose the mode lead to the two
enantiomeric structures. The rotational barriers were
obtained as the difference between the total energies,
including the zero-point and thermal corrections, of the
minima and the two transition states.
10
0
40
20
30
t / min
Figure 2. Experimental (bottom) and simulated (top) chromatograms
of 2a on a chiral stationary phase. Experimental: Chiralpak AD
250 · 4.6 mm i.d. column; eluent hexane/isopropanol 80/20; tempera-
ture 268 K; flow rate 1.0 mL/min; UV at 254 nm. Simulated: N1
1370; N2 ¼ 1426; km ¼ 0:15 minꢀ1
¼
.
apparent rate constant for the enantiomer interconver-
sion and the corresponding energy barrier DG2#68
¼
19:7 ꢁ 0:2 kcal molꢀ1 12
.
The results obtained for the energies are reported in
Tables 2 and 3 for the B3LYP/6-31G(d), and B3LYP/6-
311+G(d,p) calculations. Figure 3 shows all the sta-
tionary points found. Two minimum energy structures
were found for the non planar ground state of 2b
together with two transition states: (Z)-TS and (E)-TS.
The rotational barrier of biphenylic derivative 2a was
evaluated under aggregating conditions by dynamic
NMR.
Coalescence of the diastereomeric signals due to aro-
matic protons at the 20 position was observed at 363 K.
This temperature and the value of the rate of enantio-
merisation at the coalescence temperature kc ¼ 77:0 sꢀ1
obtained by Eq. 1 were used in the Eyring equation13
and yielded DG#363 ¼ 18:3 ꢁ 0:2 kcal molꢀ1 for the rota-
tional barrier.
The two minima are very close in energy (see Tables 2
and 3) and their relative stabilities are reverted by going
from the 6-31G(d) basis set to the larger one. From a
structural point of view, the two minima essentially
differ by the relative positions of the CH2OCOCH3 side
chain and the meta-NH2 group. At the lower level of
kc ¼ 2:22Dv
2.1. Theoretical calculation
ð1Þ
Table 2. Total energies from the DFT calculations on 2b
B3LYP/6-31G(d)
E,a a.u.
B3LYP/6-311+G(d,p)
E,a a.u.
In a previous paper we showed that the rotational bar-
rier of a substituted biphenyl can be reliably evaluated
by DFT calculations at the B3LYP/6-31G(d) level of
theory.14 The results obtained at such a level of theory
were almost coincident with those obtained at the higher
B3LYP/6-311+G(d,p) level of theory. Furthermore, the
results from the DFT calculations were in good agree-
ment with those obtained at the MP2/6-31G(d) level of
theory. Our observation of the good behaviour of the
DFT approach was in accordance with results obtained
by other authors in the calculations of rotational bar-
riers in biphenyls.15
Minimum 1
Minimum 2
(Z)-TS
)840.896862
)840.897706
)840.869137
)840.865477
)841.141891
)841.141639
)841.112564
)841.109153
(E)-TS
a Zero-point and thermal corrections (at 298.15 K) included.
Table 3. Relative energies obtained from the DFT calculations on 2b
B3LYP/6-31G(d)
DE, kcal molꢀ1
B3LYP/
6311+G(d,p) DE,
kcal molꢀ1
Minimum 1–minimum 2
(Z)-TS-(E)-TS
0.53
)2.29
17.40
17.93
19.69
20.22
)0.16
)2.14
18.40
18.24
20.54
20.39
Therefore, the same DFT approach was used herein and
the calculations for the rotational barrier of 2b were
carried out with both basis sets in order to verify if, also
in this case, the results obtained with the smaller one
were coincident with those obtained with the larger one.
(Z)-TS-minimum 1
(Z)-TS-minimum 2
(E)-TS-minimum 1
(E)-TS-minimum 2

990
R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
Table 4. Rotational barriers relative to the (Z)-transition state, aver-
aged according to the Winstein–Holness equation (see text for details)
B3LYP/6-31G(d) DEWH
,
B3LYP/6-311+G(d,p) DEWH,
kcal molꢀ1
kcal molꢀ1
17.72
18.33
equation.18 By using such an equation and under the
assumption that DE ꢂ DG, we were able to obtain an
ꢁaveragedꢀ rotational barrier that takes into account
both processes. Such averaged barriers are reported in
Table 4.
In Table 5, the experimental values obtained for the
rotational barrier of 2a are reported together with the
computational values obtained for the rotational barrier
of 2b.
The two experimental values for 2a, obtained by two
different techniques at different temperatures, differ by
1.4 kcal molꢀ1 with the value obtained in the micellar
aqueous phase by dynamic NMR being the lower one.
This can be explained if we keep in mind that a negative
value for the DS of activation should be expected
because in transition states, due to their quasi-planar
structure, the rotation of the NH2 and CH2OCOR
groups may be somewhat restricted. In the micellar
phase, due to the specific orientation of the solute,
locked by specific interactions with the aggregate, the
rotational freedom of the side groups should be lower
than in a conventional solvent. Therefore a less negative
DS of activation should be expected with a corres-
ponding lower barrier, as observed.
Figure 3. Two orthogonal view of each of the stationary points found
for 2b.
theory the dihedral angle C2–C1–C10–C20 between the
two phenyl rings was found to be 74.3ꢁ in the minimum
1 and )116.2ꢁ in minimum 2. With the larger 6-
311+G(d,p) basis set, the values were 83.4ꢁ and )110.3ꢁ,
respectively.
Not surprisingly, the computational values obtained at
the higher level of theory, are closer to the experimental
one obtained in the micellar phase. In fact the computed
ones, being obtained as differences of the total energies
corrected for the zero-point and thermal corrections
differences (at 298.15 K), do not contain the entropic
contributions to the barrier.
The (Z)-transition state was found to be more stable
than the (E) one at both levels of theory. Therefore, with
the barriers relative to the (Z)-transition state being the
lowest, these are the ones to compare with the experi-
mental data. Since two minimum structures were found
for compound 2b, in order to compare the two com-
puted rotational barriers with the experimental one, we
had to take into account that both minima 1 and 2 can
racemise independently passing through the lowest
(Z)-transition state. Both processes contribute to the
experimentally measured racemisation rate constant.
Such a rate constant, under the assumption that the
equilibration process between the two minima is fast
with respect to the racemisation process, is related to the
microscopic rate constants by the Winstein–Holness
2.2. Recognition experiments
1H NMR recognition experiments performed in an
aqueous solution of biphenylic derivative 1a, in the
presence of surfactants 3 or 4, did not give any evidence
for the recognition phenomena. The spectra relative to
aqueous solutions of biphenylic derivative 2a, in the
presence of either surfactants 4a or 4b show diastereo-
meric signals for some aromatic protons. In fact as
shown in Figure 4, the aromatic region of the NMR
spectrum of an aqueous solution of 2a in the presence of
Table 5. Rotational barriers of compounds 2 as obtained by experimental and theoretical approaches
Compound
Source
Rotational barrier, kcal molꢀ1
Solvent, temperature K
2a
2a
2b
2b
Dynamic HPLC
Dynamic NMR
19.7 0.2
18.3 0.2
17.7
Hexane/isopropanol 8/2, 268
Micellar aqueous phase, 363
Vacuum, 298
B3LYP/6-31G(d) calculations
B3LYP/6-311+G(d,p) calculations
18.3
Vacuum, 298

R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
991
difference in the extent of binding of the enantiomers to
the chiral aggregates.
5’
4
5
6’
3
2’
2’ 4’
(ppm)
6.20
As far as the NMR experiments are concerned, it is
worthwhile to note two points: the first one being that
chiral recognition of 2a enantiomers concerns the same
portion of the biphenylic derivative in all the considered
aggregates, namely, protons at the 20 (surfactants 3 and
4) and 40 positions (surfactants 4). The second point is
the absence of chiral discrimination of enantiomers of
compound 1a either by the cationic or anionic micelles.
The different positions of one of the amino groups on
the biphenylic molecule is responsible on one hand for
the absence of discrimination of the enantiomers of
compound 1a and on the other hand for the different
mode of interaction of the enantiomers of compound 2a.
The amino group on the 30 position should therefore be
responsible for the favourable locking of the solute in
the chiral environment of both the cationic and the
anionic aggregates.
6.40
6.60
6.80
7.00
(ppm)
7.00
6.80
6.60
6.40
6.20
Figure 4. Aromatic region of the H,H-COSY spectrum of an aqueous
solution 2.0 mM in 2a and 10 mM in 4a.
CD spectra were run on the same solution used in NMR
experiments in order to see if in the absence of derace-
misation, as demonstrated by NMR experiments, they
could put in evidence any induced effect.19 No chiral
effect was observed by CD in any of the aqueous
micellar solutions.
the aggregates formed by 4a showed a number of signals
and a multiplicity higher than expected. The H,H-COSY
experiment as reported in Figure 4 allowed us to assign
aromatic protons and thus observe which protons were
more influenced by the diastereomeric interactions with
the chiral aggregates, that is those at the 20 and 40
positions.
In the spectrum of an aqueous solution of biphenylic
derivative 2a in the presence of anionic surfactant 3,
chiral diasteromeric interactions yielded diastereomeric
NMR signals only for the enantiomeric protons at the 20
position (Fig. 5). In all cases (in the presence of the
anionic and the cationic surfactants) the intensity ratio
of the integrals of diastereomeric signals was 1. As the
rotational barrier was such to allow interconversion
under the experimental conditions, the absence of
deracemisation indicates that there is no appreciable
3. Conclusion
In conclusion chiral recognition was observed by NMR
in chiral micellar aggregates (either cationic or anionic)
on racemic mixture of chiral biphenylic derivative 2a,
whereas discrimination was not observed on its regio-
isomer 1a. The mode of interaction with the aggregate,
and the consequent discrimination, seems therefore
dictated by the different position of the amino group.
5’
4
5
6’
3
2’
4’
4. Experimental
(ppm)
NMR spectra were run on a Bruker AC 300 P spec-
trometer operating at 300.13 and 75.47 MHz for 1H and
13C, respectively, equipped with a sample tube thermo-
stating apparatus. Signals were referenced with respect
to TMS (d ¼ 0:000 ppm) being used as an internal
standard in CDCl3 and to DOH (d ¼ 4:750 ppm at
298 K and d ¼ 4:642 ppm at 308 K) in D2O.
1H NMR recognition experiments were performed on
aqueous solutions of: (a) 2.0 mM biphenylic derivative
1a or 2a in the presence of 10 mM N-hexadecyl-N,N-
dimethyl-N-(S)-(1-phenyl)ethylammonium bromide 4a
(at 308 K, well above the Krafft point), (b) 6.0 mM
biphenylic derivative 1a or 2a in the presence of 36 mM
N-dodecyl-N,N-dimethyl-N-(S)-(1-phenyl)ethylammo-
nium bromide 4b (at 298 K), (c) 18 mM biphenylic
6.60
6.80
7.00
7.20
(ppm)
7.00
6.80
6.60
Figure 5. Aromatic region of the H,H-COSY spectrum of an aqueous
solution 18 mM in 2a and 100 mM in 3.

992
R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
derivative 1a or 2a in the presence of 100 mM 3 (at
298 K). In all cases the ratio between the micellised
surfactant and solute was 5.
2-Carboxymethyl-20,6-dinitrobiphenyl. 2-Bromo-3-nitro-
methylbenzoate (0.5 g, 4 mmol) and 1.0 g of 1-iodo-2-
nitrobenzene (2 mmol) were added to 10 mL of dry
DMF. To the reaction mixture, heated at 353 K in an
inert atmosphere, 1.0 g of finely powdered Cu (Fluka)
was added while stirring. The reaction was monitored by
TLC until the disappearance of 1-iodo-2-nitrobenzene.
The reaction mixture was then allowed to cool and fil-
tered. After removal of the solvent in vacuum, the res-
idue was diluted with CH2Cl2. The organic solution was
washed with water, aqueous ammonia solution (10%),
brine and then dried over Na2SO4. Purification on silica
gel using hexane/Et2O/CH2Cl2 (10:5:1) as eluent yielded
350 mg (59%) of a yellow solid. Mp 408–411 K. 1H
NMR, d (CDCl3): 3.616 (s, CH3, 3H), 7.11–7.15 (m, ar,
1H), 7.56–7.65 (m, ar, 2H), 7.580 (t, ar, 1H, Jo ¼ 8:2 Hz,
Jo ¼ 7:9 Hz), 8.218 (dd, ar, 1H, Jo ¼ 7:9 Hz, Jm ¼
1:4 Hz), 8.275 (dd, ar, 1H, Jo ¼ 8:2 Hz, Jm ¼ 1:4 Hz),
8.29–8.34 (m, ar, 1H). 13C NMR, d (CDCl3): 52.54,
124.47, 127.76, 128.73, 129.22, 129.49, 131.20, 131.84,
133.40, 134.66, 134.83, 147.82, 148.64, 165.04.
The dynamic NMR experiments were performed on a
1
Bruker AC 300 P spectrometer. H NMR spectra were
performed at various temperatures between 295 and
363 K on an aqueous solution of 4a (10.0 mM) and of 2a
(2.0 mM). The Dm value between the diastereomeric
signals relative to the aromatic protons at the 20 position
in the spectrum registered at 295 K was used in Eq. 1 for
obtaining the enantiomerisation rate constant at the
coalescence temperature.23
CD spectra were registered on a Jasco spectropolari-
meter J-715 using quartz cells of 1 and 0.1 cm path length.
Optical rotation measurements were carried out on a
Perkin Elmer-241 polarimeter using a cell of 10 cm path
length.
HPLC separation of the enantiomers of 1a and 2a was
carried out on a Chiralpak AD column (250ꢃ4.6 mm
i.d.). For the dynamic HPLC experiments, the column
was placed in a cooling bath with temperature con-
trolled within 0.2 K while placing a 50 cm long inlet
capillary inside the cooling liquid to ensure thermal
equilibration of the mobile phase. Retention times for
the enantiomers of 1a: t1 ¼ 11 min, t2 ¼ 16 min using
hexane/2-propanol 80/20 as the mobile phase, delivered
at 1.0 mL/min, T ¼ 297 K. Isolation of the first eluted
enantiomer of 1a for CD characterisation studies was
carried out on the same column by three replicate
injections of 1 mg/mL (0.5 mL each run) solutions via a
2 mL loop.
2-Carboxy-20,6-dinitrobiphenyl. 2-Carboxymethyl-20,6-
dinitrobiphenyl (0.5 g, 1.65 mmol) was added to 20 mL
of ethanol and 10 mL of an aqueous solution of NaOH
(5%). After 3 h under reflux and stirring, the reaction
mixture was allowed to cool and was acidified with HCl
(1.0 M). The mixture was extracted with CHCl3 and the
organic layer washed with brine and dried over Na2SO4.
Removal of chloroform by rotary evaporation yielded
1
0.46 g (97%) of a low melting yellow solid. H NMR,
d (CDCl3): 7.085 (d, ar, 1H, Jo ¼ 6:8 Hz), 7.57–7.64 (m,
ar, 2H), 7.658 (t, ar, 1H, Jo ¼ 8:1 Hz), 8.220 (d, ar, 1H,
Jo ¼ 8:1 Hz), 8.27–8.33 (m, ar, 2H). 13C NMR,
d (CDCl3): 124.62, 128.78, 128.85, 129.39, 129.41,
131.52, 133.63, 135.45, 147.81, 148.85, 169.60.
Cmc measurements were carried out by isothermal
titration microcalorimetry (ITC). In ITC titrations the
heat effects accompanying mixing of aliquots of surfac-
tant solution (msurf ꢄ cmc) with solvent or dilute sur-
factant solutions were measured in TAM 2277
(Thermometric, Sweden) microcalorimeter.
2-Hydroxymethyl-20,6-dinitrobiphenyl. B2H6 in THF
(2 mL, 1 M) solution were added dropwise to a solution
of 0.2 g (0.7 mmol) of 2-carboxy-20,6-dinitrobiphenyl in
3 mL of dry THF, while stirring in an inert atmosphere.
After two hours at room temperature, the reaction
mixture was treated with wet THF, until the develop-
ment of H2, and then brine. Removal of the solvent
from the organic layer yielded 0.2 g (92%) of brown oil.
1H NMR, d (CDCl3): 4.292 (s, CH2, 2H), 7.20 (dd, ar,
1H, Jo ¼ 7:4 Hz, Jm ¼ 1:4 Hz), 7.56–7.70 (m, ar, 3H),
7.86 (d, ar, 1H, Jo ¼ 8:0 Hz), 8.05 (dd, ar, 1H,
Jo ¼ 8:0 Hz, Jm ¼ 1:3 Hz), 8.23 (dd, ar, 2H, Jo ¼ 7:8 Hz,
Jm ¼ 1:4 Hz). 13C NMR, d (CDCl3): 62.21, 123.57,
124.85, 128.93, 129.47, 130.47, 130.85, 131.91, 132.45,
133.71, 140.85, 147.43, 147.80.
Krafft point and Krafft temperatures of surfactants 4 were
measured by conductivity measurements according to a
described procedure.9 Weighted quantities of surfactant
4a and 4b were heated to obtain clear solutions. These
were kept at 277 K for 24 h before measurement. During
measurements the solutions were continually stirred
while the temperature was raised at a rate of 0.05 K/min.
In the conductivity/temperature plots, the Krafft point
was estimated by the first break and the Krafft temper-
ature by the second one. The following values were
obtained for 4b: Krafft point ¼ 295.4 K; Krafft temper-
ature ¼ 304.6 K (20 mM solution). Surfactant 4a has a
Krafft point <277 K.
2,20-Dinitro-6-(octanoyloxymethyl)biphenyl. Octanoyl
chloride (120 lL, 0.7 mmol) and 60 lL of pyridine were
added, while stirring at room temperature, to 0.2 g
(0.7 mmol) of 2-hydroxymethyl-20,6-dinitrobiphenyl in
15 mL of CH2Cl2. After 48 h, the reaction mixture was
washed with an aqueous solution of HCl (1.0 M) and
then a saturated aqueous solution of NaHCO3. The
organic layer was dried over Na2SO4. After removal of
solvent, purification of the residue on silica gel, using
Et2O/CHCl3 (60:40) as eluent, yielded 0.24 g (80%) of
2-Bromo-3-nitromethylbenzoate was prepared as previ-
ously described.20 Mp 350–351 K. 1H NMR, d (CDCl3):
3.961 (s, 3H, CH3), 7.507 (t, 1H, Jo ¼ 8:0 Hz), 7.746 (dd,
1H, Jm ¼ 1:6 Hz, Jo ¼ 8:0 Hz), 7.838 (dd, 1H,
Jm ¼ 1:6 Hz, Jo ¼ 8:0 Hz). 13C NMR, d (CDCl3): 53.07,
112.72, 126.64, 128.19, 135.71, 151.93, 165.49.

R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
993
yellow oil. 1H NMR, d (CDCl3): 0.836 (t, CH3, 3H,
J ¼ 5:8 Hz), 1.238 (m, aliphatic chain, 10H), 1.638 (m,
CH2, 2H), 2.429 (t, CH2a, 2H, J ¼ 7:3 Hz), 4.57–4.85
(AB system, CH2OCO, 2H, J ¼ 13:0 Hz), 7.242 (dd, ar,
1H, Jo ¼ 7:0 Hz, Jm ¼ 1:3 Hz), 7.58–7.75 (m, ar, 3H),
7.774 (dd, ar, 1H, Jo ¼ 7:7 Hz, Jm ¼ 1:3 Hz), 8.132 (d, ar,
1H, Jo ¼ 8:2 Hz, Jm ¼ 1:3 Hz), 8.275 (dd, ar, 1H,
Jo ¼ 8:2 Hz, Jm ¼ 1:3 Hz).
62.04, 65.84, 123.25, 123.63, 129.50, 129.62, 132.01,
134.72, 136.54, 141.51, 148.16, 149.27.
2,30-Dinitro-6-(octanoyloxymethyl)biphenyl. 2-Hydroxy-
methyl-30,6-dinitrobiphenyl (0.2 g, 0.7 mmol) was ester-
ified with octanoyl chloride according to the procedure
described for 2,20-dinitro-6-(octanoyloxymethyl)biphe-
nyl. The residue was purified on silica gel, using CHCl3
1
as eluent, and yielded a yellow oil (80%). H NMR, d
2,20-Diamino-6-(octanoyloxymethyl)biphenyl 1a. SnCl2 Æ
2H2O (0.57 g, 2.5 mmol) was added to 0.10 g
(CDCl3): 0.858 (t, CH3, 3H, J ¼ 6:8 Hz), 1.243 (m, CH2,
10H), 2.274 (t, CH2, 2H, J ¼ 7:4 Hz), 4.802 (AB system,
CH2, 2H, J ¼ 13:0 Hz), 7.54–7.66 (m, ar, 3H), 7.776 (dd,
ar, 1H, Jo ¼ 8:0 Hz, Jm ¼ 1:2 Hz), 7.956 (d, ar, 1H,
Jo ¼ 8:0 Hz, Jm ¼ 1:2 Hz), 8.152 (t, ar, 1H, Jm ¼ 1:8 Hz,
Jm ¼ 2:2 Hz), 8.294 (dd, ar, 1H, Jo ¼ 8.0 Hz Jm ¼ 1:5 Hz,
Jm ¼ 2:2 Hz).
(0.25 mmol)
of
2,20-dinitro-6-(octanoyloxymethyl)
biphenyl in 10 mL of absolute ethanol. After 2 h while
stirring at 343 K, the reaction mixture was poured into a
beaker with ice and made alkaline with NaOH (12.0 M).
The aqueous solution was extracted with ethyl acetate
and the organic layer dried over Na2SO4. After removal
of solvent, purification of the residue on silica gel, using
ethyl acetate/hexane (70:30) as eluent, yielded the target
product (58%). 1H NMR, d (CDCl3): 0.870 (t, CH3, 3H.
J ¼ 6:5 Hz), 1.250 (m, chain, 10H), 1.556 (m, CH2b,
2H), 2.243 (t, CH2a, 2H, J ¼ 7:4 Hz), 3.538 (s, NH, 4H),
4.793 (AB system, CH2 OCO, 2H, J ¼ 12:9 Hz),
6.73–6.83 (m, ar, 3H), 6.850 (d, ar, 1H, Jo ¼ 7:5 Hz),
6.993 (d, ar, 1H, Jo ¼ 7:5 Hz), 7.090 (t, ar, 1H,
Jo ¼ 7:6 Hz), 7.100 (t, ar. 1H, Jo ¼ 7:5 Hz).13C NMR, d
(CDCl3): 14.05, 22.56, 24.86, 28.89, 29.06, 31.62, 34.23,
64.47, 115.10, 115.60, 118.39, 118.89, 128.70, 129.96,
130.80, 135.94, 144.42, 144.84, 173.42. ES-MS ¼ 341
(MH+).
2,30-Diamino-6-(octanoyloxymethyl)biphenyl 2a. 2,30-Di-
nitro-6-(octanoyloxymethyl)biphenyl (0.1 g, 0.25 mmol)
was reduced according to the procedure reported for
2,20-diamino-6-(octanoyloxymethyl)biphenyl. The resi-
due was purified on silica gel, using CHCl3 as the eluent,
1
and yielded a yellow oil (13%). H NMR, d (CDCl3):
0.866 (t, CH3, 3H, J ¼ 6:5 Hz), 1.258 (m, CH2 chain,
8H), 1.575 (m, CH2b, 2H), 2.256 (t, CH2a, 2H,
J ¼ 7:4 Hz), 3.632 (s, NH, 1H), 4.813 (s, CH2OCO, 2H),
6.557 (t, ar, 1H, Jm ¼ 1:5 Hz, Jm ¼ 1:8 Hz), 6.622 (dd, ar,
1H Jo ¼ 7:7 Hz, Jm ¼ 2:4 Hz), 6.667 (dd, ar, 1H,
Jo ¼ 8:0 Hz, Jm ¼ 2:4 Hz), 6.721 (d, ar, 1H, Jo ¼ 8:0 Hz),
6.830 (d, ar, 1H, Jo ¼ 8:0 Hz), 7.137 (t, ar, 1H,
Jo ¼ 8:0 Hz), 7.210 (t, ar, 1H, Jo ¼ 8:0 Hz). 13C NMR, d
(CDCl3): 14.11, 22.63, 24.99, 28.99, 31.69, 34.39, 64.49,
114.53, 114.95, 116.23, 118.40, 119.96, 127.57, 128.23,
130.11, 134.79, 137.42, 144.27, 144.96, 147.03, 173.55.
ES-MS ¼ 341 (MH+).
2-Carboxymethyl-30,6-dinitrobiphenyl. 2-Bromo-3-nitro-
methylbenzoate (1.0 g, 8.0 mmol) and 1.0 g (2.0 mmol) of
1-iodo-3-nitrobenzene were coupled according to the
above described Ulmann procedure (preparation of
2-carboxymethyl-20,6-dinitrobiphenyl). The final residue
was purified on silica gel, using hexane/Et2O/toluene
(50:40:10), and yielded a white solid (34%) mp ¼ 380–
384 K. 1H NMR, d (CDCl3): 7.51–7.58 (m, ar, 2H),
7.645 (t, ar, 1H, Jo ¼ 8:0 Hz), 8.000 (dd, ar, 1H,
Jo ¼ 8:0 Hz, Jm ¼ 1:3 Hz), 8.074 (t, ar, 1H, Jm ¼ 1:2 Hz),
8.145 (dd, ar, 1H, Jo ¼ 8:0 Hz, Jm ¼ 1:3 Hz) 8.234 (m, ar,
1H, Jo ¼ 6:9 Hz). 13C NMR, d (CDCl3): 52.62, 123.18,
123.37, 126.79, 129.49, 133.09, 133.57, 133.78, 134.39,
136.67, 147.74, 150.35, 165.52.
(S)-N,N-Dimethyl-N-hexadecyl-N-(1-phenyl)ethylammo-
nium bromide 4a. (S)-N,N-dimethyl-a-methylbenzylamine
was quaternised with 1-bromohexadecane according to
a reported procedure.8 1H NMR, d (CDCl3): 0.833 (t,
CH3, 3H, J ¼ 6:5 Hz), 1.249 (m, CH2 chain, 26H), 1.783
(m, CH2, 2H), 1.830 (d, CH3, 3H, J ¼ 7:1 Hz), 3.160 (s,
CH3, 3H), 3.200 (s, CH3, 3H), 3.470 (t, CH2, 2H,
J ¼ 7:1 Hz), 5.389 (q, CH, 1H, J ¼ 7:1 Hz), 7.38–7.47
20
(m, ar, 3H), 7.620 (m, ar, 2H). ½aꢅ )19 (c 10, EtOH).
D
cmc ¼ 0.24 mmol/kg.
2-Carboxy-30,6-dinitrobiphenyl. 2-Carboxymethyl-30,6-
dinitrobiphenyl (0.5 g, 1.65 mmol) was hydrolysed as
above described for 2-carboxy-20,6-dinitrobiphenyl.
Removal of the solvent by rotary evaporation yielded a
(S)-N,N-Dimethyl-N-dodecyl-N-(1-phenyl)ethylammo-
nium bromide 4b. (S)-N,N-Dimethyl-a-methylbenzyl-
amine was quaternised with 1-bromododecane
according to a reported procedure.8 1H NMR, d
(CDCl3): 0.864 (t, CH3, 3H, J ¼ 6:5 Hz), 1.233 (m,
CH2 chain, 16H), 1.326 (m, CH2 2H), 1.767 (m, CH2,
2H), 1.826 (d, CH3, 3H, J ¼ 7:1 Hz), 3.133 (s, CH3,
3H), 3.175 (s, CH3, 3H), 3.497 (t, CH2, 2H, J ¼ 7:1 Hz),
5.488 (q, CH, 1H, J ¼ 7:1 Hz), 7.36–7.46 (m, ar, 3H),
7.590 (m, ar, 2H). Elemental analysis C 66.30%;
1
white low melting solid (97%). H NMR, d (CDCl3):
7.45–7.61 (m, ar, 2H), 7.682 (t, ar, 1H, Jo ¼ 8:1 Hz),
8.042 (dd, ar, 1H, Jo ¼ 8:1 Hz, Jm ¼ 1:2 Hz), 8.077 (t, ar,
1H, Jm ¼ 0:9 Hz), 8.22–8.26 (m, ar, 2H).
2-Hydroxymethyl-30,6-dinitrobiphenyl. 2-Carboxy-30,6-
dinitrobiphenyl (0.2 g, 0.7 mmol) was reduced as above
described for 2-hydroxymethyl-20,6-dinitrobiphenyl.
Work up of the reaction yielded 0.18 g (92%) of brown
oil. 1H NMR, d (CDCl3): 4.362 (m, CH2, 2H), 7.50–7.68
(m, ar, 4H), 7.901 (d, ar, 1H, Jo ¼ 7:9 Hz), 8.101 (t, ar,
1H, Jm ¼ 1:7 Hz); 8.260 (dd, ar, 1H, Jo ¼ 8:0 Hz,
Jm ¼ 1:7 Hz, Jm ¼ 0:8 Hz). 13C NMR, d (CDCl3): 151.99,
H 10.16%; N 3.69% (expected C 66.31%; H 10.12%;
20
D
N 3.52%). ½aꢅ )21.6 (c 9.8, EtOH). cmc ¼ 7.7 mmol/
kg.
Sodium-N-dodecanoyl-L-prolinate 3 was prepared and
characterised as previously reported.7

994
R. Andreani et al. / Tetrahedron: Asymmetry 15 (2004) 987–994
Hunter, R. J. Foundations of Colloid Science, Vol. 1;
ꢁ
Clarendon: Oxford, 1987; (e) Skerjanc, J.; Kogej, K.;
Acknowledgements
Cerar, J. Langmuir 1999, 15, 5023–5028.
11. (a) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001,
This work was carried out in the frame of a European
project of Action COSTD11 entitled ꢁChiral Recogni-
tion in Self-assembled Systemsꢀ.
€
30, 145–157; (b) Wolff, C.; Konig, W. A.; Roussel, C.
Liebigs Ann. 1995, 5, 781–786; (c) Wolff, C.; Hochmuth,
€
D. H.; Konig, W. A.; Roussel, C. Liebigs Ann. 1996, 3,
357–363.
One of the authors (C.V.) is grateful for the financial
support from PRIN 2003 contract no 2003039537.
12. (a) Trapp, O.; Schoetz, G.; Schurig, V. Chirality 2001, 13,
403–414; (b) Gasparrini, F.; Misiti, D.; Pierini, M.; Villani,
C. Tetrahedron: Asymmetry 1997, 8, 2069–2073.
References and notes
13. Friebolin, H. Basic One and Two-Dimensional NMR
Spectroscopy. 3rd revised ed.; VCH: Weinheim, 1998; pp
301–311.
14. Ceccacci, F.; Mancini, G.; Mencarelli, P.; Villani, C.
Tetrahedron: Asymmetry 2003, 14, 3117–3122.
1. Groves, J. T.; McConnel, H. M. Biophys. J. 1996, 70,
1573–1574.
2. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
ꢂ
15. (a) Biedermann, P. U.; Schurig, V.; Agranat, I. Chirality
1997, 9, 350–353; (b) Grein, F. J. Phys. Chem. A 2002, 106,
3823–3827; (c) Arulmozhiraja, S.; Selvin, P. C.; Fujii, T.
J. Phys. Chem. A 2002, 106, 1765–1769; (d) Arulmozhi-
raja, S.; Fujii, T. J. Chem. Phys. 2001, 115, 10589–10594.
16. 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.; Raghava-
chari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.;
Baboul, A. G.; 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.; Nanayak-
kara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.
Gaussian 98, Revision A.7, Gaussian, Pittsburgh, PA, 1998.
17. Schaftenaar, G.; Noordik, J. H. J. Comput. Aided Mol.
Des. 2000, 14, 123–134.
Palacios, J. C. Tetrahedron: Asymmetry 2000, 11, 2845–
2874.
3. Maier, N. M.; Franco, P.; Lindner, W. J. Chromatogr. A
2001, 906, 3–33, and references cited therein.
4. (a) Borocci, S.; Erba, M.; Mancini, G.; Scipioni, A.
Langmuir 1998, 14, 1960–1962; (b) Nakagawa, H.;
Kobori, Y.; Yoshida, M.; Yamada, K. Chem. Comm.
2001, 2691–2693; (c) Borocci, S.; Ceccacci, F.; Galantini,
L.; Mancini, G.; Monti, D.; Scipioni, A.; Venanzi, M.
€
Chirality 2003, 15, 441–447; (d) Wolff, C.; Konig, W. A.;
Roussel, C. Chirality 1995, 7, 610–611.
5. Borocci, S.; Mancini, G.; Cerichelli, G.; Luchetti, L.
Langmuir 1999, 15, 2627–2630.
6. (a) Belogi, G.; Croce, M.; Mancini, G. Langmuir 1997, 13,
2903–2904; (b) Bella, J.; Borocci, S.; Mancini, G. Lang-
muir 1999, 15, 8025–8031.
7. (a) Cleij, M. C.; Drenth, W.; Nolte, R. J. M. J. Org. Chem.
1991, 56, 3833–3891; (b) Moss, R. A.; Sunshine, W. L.
J. Org. Chem. 1974, 39, 1083–1088.
8. Moss, R. A.; Sunshine, W. L. J. Org. Chem. 1974, 39,
1083–1089.
ꢂ
ꢂ
ꢂ
ꢁ ꢂ
9. (a) Stilipon Filipovic-Vincelovic, N.; Babic-Ivancic, V.;
Smit, I. J. Colloid Interf. Sci. 1996, 177, 646–657, and
ꢁ
18. Eliel, E. L. S.; Wilen, H. Stereochemistry of Carbon Com-
pounds; Wiley: New York, 1994; pp 647–655.
19. Allenmark, S. Chirality 2003, 15, 409–422.
20. (a) Whitmore, F. C.; Culhane, P. J.; Neher, H. T. Org.
Synth. Coll. 1927, Vol. I, 48; (b) Culhane, P. J. Org. Synth.
1927, Vol. I, 120.
references cited therein; (b) Bales, B. L.; Benrraou, M.;
Zana, R. J. Phys. Chem. B 2002, 106, 9033–9035.
10. (a) Lah, J.; Pohar, C.; Vesnaver, G. J. Phys. Chem. B 2000,
104, 2522–2526; (b) Lah, J.; Maier, N. M.; Lindner, W.;
Vesnaver, G. J. Phys. Chem. B 2001, 105, 1670–1678; (c)
Philips, J. N. Trans. Faraday Soc. 1955, 51, 561; (d)