Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

Article abstract of DOI:10.1007/s12039-010-0090-z

Efficient use of the readily accessible chiral C ₂-symmetric acyclic diamines (1-2) as well as macrocyclic amines (3-5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents (CSA) for the determination of enantiomeric excess

Full text of DOI:10.1007/s12039-010-0090-z

J. Chem. Sci., Vol. 122, No. 4, July 2010, pp. 561–569. © Indian Academy of Sciences.
Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating
agents for carboxylic acids
MARIAPPAN PERIASAMY*, MANASI DALAI and MEDURI PADMAJA
School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad 500 046
e-mail: mpsc@uohyd.ernet.in
MS received 27 August 2009; revised 20 May 2010; accepted 16 June 2010
Abstract. Efficient use of the readily accessible chiral C -symmetric acyclic diamines (1–2) as well as
2
macrocyclic amines (3–5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents
(CSA) for the determination of enantiomeric excess of representative carboxylic acids (6–7) and an
amino acid derivative (8) is illustrated. The enantiomeric composition of different carboxylic acids esti-
1
mated here by the H NMR method, based on the integration of the corresponding methine proton signals
are in good correlation with that determined using HPLC method. The data are in accordance with the
formation of multimolecular diastereomeric complexes in solution, which render good splitting of NMR
signals for the enantiomers of representative carboxylic acids as well as for N-Ts-phenylglycine (up to
ΔΔδ = 0⋅295 ppm, 118 Hz).
Keywords. Chiral 1,2-cyclohexyl diamines; macrocyclic amines; chiral solvating agents; enantiomeric
purity; chiral carboxylic acids.
8
1. Introduction
steps. Besides the starting chiral materials, analytes
and the CSA could be easily recovered after the
measurement. The wide variety of chiral shift re-
In view of the importance of chiral organic com-
1–4
9
pounds in biological and pharmaceutical chemistry,
agents, such as lanthanide complexes, crown
10
11
12
13
there is increasing requirement for fast and accurate
methodologies for the determination of enantiomeric
composition of these chiral compounds. Among the
various available methods, NMR spectroscopy has
the advantages of easy performance and accessibi-
ether, cyclodextrin, porphyrins, macrocycles,
14
and others have already been reported. However,
there are only few reports on the development of ef-
ficient chiral shift reagents for carboxylic acids, in
15
spite of their importance in chemistry.
5
lity with no need for special equipment apart from
Chiral macrocyclic compounds have been recog-
nized as successful and promising chiral selectors
for molecular recognition, mainly because of their
inherent reduced flexibility and complexation abil-
the common NMR spectrometers. As enantiomers
cannot be distinguished in an achiral environment,
these techniques require the modification of the sub-
strate with a chiral auxiliary, which would convert
the mixture of enantiomers into a mixture of di-
astereomeric molecular (covalent, chiral derivatizing
agent, CDA) or supramolecular (non-covalent, chiral
16
17
ity. Recently, Tanaka et al reported that chiral
macrocyclic amine functions as highly sensitive
chiral shift reagent for several kinds of secondary
alcohols, cyanohydrins and propargyl alcohols.
However, these macrocycles are not useful as chiral
shift reagents for carboxylic acids, without introduc-
tion of both hydrogen bond acceptor and donor
group in the host macrocycles for multiple binding
6
solvating agents, CSA) complexes. Ideally, these
diastereomeric species will show chemical shift non-
equivalence of some of their NMR signals, allowing
the determination of the enantiomeric composition
of the substrate by the direct integration of these
18
with the carboxylic acids. Accordingly, in con-
7
bands. The advantage of using non-covalent chiral
tinuation of our research efforts towards the synthe-
19
solvating agents relies on the possibility of carrying
sis of chiral macrocycles and other chiral N-alkyla-
20
out the experiment in situ, without purification
ted
amines
containing
trans-1,2-diamino-
cyclohexane moiety (figure 1), we have examined
their use as chiral solvating agents for the determi-
*For correspondence
561

562
Mariappan Periasamy et al
Figure 1. Structures of the receptors studied 1–5.
nation of enantiomeric excess of carboxylic acids by was neutralized with 2N NaOH (15 mL) and
1
H NMR spectroscopy. The results are presented extracted with dichloromethane (2 × 15 mL). The
here.
combined organic extracts were washed with brine
(15 mL), dried over anhydrous sodium sulphate and
evaporated to give the permethylated product 4.
2. Experimental
2 5
Yield: 1⋅58 g (90%); m.p.: 178–180°C; [α] = –
D
16⋅9 (c 0⋅9, CH Cl ); IR (KBr): 3028, 2926, 1450,
2 2
2.1 Materials, method and instruments
Infrared spectra were recorded on JASCO FT–IR
–1
1
763 cm ; H-NMR (400 MHz, CDCl ) δ 1⋅15–1⋅23
3
(m, 6H), 1⋅30–1⋅40 (m, 6H), 1⋅80–1⋅85 (m, 6H),
2⋅00–2⋅05 (m, 6H), 2⋅21 (s, 18H), 2⋅72–2⋅74 (m,
1
spectrophotometer Model 5300. H NMR and
13
6H), 3⋅76 (q, J = 12⋅8 Hz, 12H), 7⋅40 (s, 12H);
C NMR spectra were recorded on Bruker AV-400
13
C-NMR (50 MHz, CDCl ) δ 25⋅9, 26⋅3, 35⋅8, 58⋅6,
3
spectrometer with chloroform-d as a solvent and
TMS as the reference (δ = 0 ppm). Coupling constants
J reported are in Hz. Elemental analyses were car-
ried out on a Flash EA 1112 series analyzer. Optical
rotations were measured in an AUTOPOL-IV auto-
matic polarimeter (readability 0⋅001). Chromatog-
raphy was carried out using Acme’s silica gel (100–
200 mesh and 230–400 mesh). The commercial
cis/trans mixture of 1,2-diaminocyclohexane was
64⋅9, 128⋅6, 139⋅3; CHN calculated: C, 78⋅5%; H,
9⋅8%; N, 11⋅4%; Found: C, 78⋅5%; H, 9⋅9%; N,
11⋅4%; MS (LCMS): C H N (m/z 734 M + 1).
48 72
6
2.3 Procedure for the synthesis of the chiral mac-
rocyclic amine (5)
To a stirred solution of (R,R)-1,2-diaminocyclo-
hexane (10 mmol, 1⋅14 g) and triethylamine
(5⋅6 mL) in dichloromethane (40 mL), isophthaloyl
chloride (10 mmol, 2 g) was added at 0°C and the
reaction mixture was allowed to stir at 25°C for
12 h. The reaction was quenched with water
(15 mL). The residues were filtered off and washed
with dichloromethane (20 mL) to obtain the insolu-
27
resolved following a reported procedure. Iso-
phthaloyl chloride was prepared from isophthalic
acid and distilled under reduced pressure. The race-
mic 2,3-diphenylsuccinic acid was synthesized fol-
28
lowing a reported procedure.
2.2 Procedure for the synthesis of chiral
macrocyclic amine (4)
ble polyamide. To
a
suspension of NaBH
4
(40 mmol, 1⋅43 g) in tetrahydrofuran (150 mL), a
solution of I (20 mmol, 4⋅8 g) in THF (30 mL) was
2
The secondary macrocyclic amine 3 (2⋅4 mmol,
1⋅5 g), formic acid (2 mL) and formaldehyde (1 mL)
were heated at 110°C for 12 h. The reaction mixture
added at 0°C under nitrogen atmosphere over
30 min. The polyamide (1 g) was added to the gen-

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids
563
erated diborane and refluxed for 24 h. The reaction according to the Job’s method of continuous varia-
was quenched with methanol and the solvents were tions. Equimolar amounts of 3 (0⋅0025 M) and (R)
evaporated. The residue obtained after evaporation or (S)-6 (0⋅0025 M) were prepared in CDCl (5 mL)
3
.
was refluxed with 10 N KOH for 6 h and the resul- These solutions were distributed among ten NMR
tant polyamine was extracted with dichloromethane tubes in such a way that the mole fractions of 3 and
(2 × 30 mL). The organic extracts were washed with 6 in the resulting solutions increased from 0⋅1 to 0⋅9.
brine (30 mL), dried over anhydrous sodium sul- The complexation induced shifts of the methine sig-
phate and the residue was evaporated to obtain the nal (Δδ) were multiplied by the mole fraction of the
polyamine. The crude amine was chromatographed acid 6 (X) and plotted against X to obtain the Job’s
on a silica gel column using chloroform:methanol plot (figure 3).
(95 : 5) to obtain the macrocyclic amine 5 in pure
1
form.
2.4c H-NMR titrations: The mandelic acid 6
[(R) or (S)] (0⋅0031 M [2⋅4 mg in 5 mL]) was dis-
–101 (c 0⋅4, CHCl ); IR (KBr) 3296, 3024, 2928, solved in CDCl and evenly distributed (0⋅5 mL)
o
2 5
Yield: 0⋅2 g (23%); m.p.: 108–110 C; [α]
=
D
3
3
–1
1
1452, 1114, 787 cm ; H-NMR (400 MHz, CDCl ) among ten NMR tubes. The first NMR tube was
3
δ 1⋅056 (m, 4H), 1⋅28 (m, 4H), 1⋅79 (m, 9H), 2⋅28 sealed without any amine. The macrocyclic amine 3
(m, 7H), 3⋅66 (d, J = 12⋅8 Hz, 4H), 3⋅96 (d, was dissolved in CDCl (0⋅039 M [51⋅5 mg in
3
J = 13⋅2 Hz, 4H), 7⋅07 (d, J = 7⋅6 Hz, 4H), 7⋅20 2 mL]) and added in increasing amounts to the NMR
13
(m, 2H), 7⋅64 (s, 2H); C-NMR (50 MHz, CDCl ) δ tubes so that the solutions with relative concentra-
3
25⋅1, 31⋅4, 50⋅8, 60⋅9, 126⋅4, 126⋅9, 127⋅7, 141⋅1; tions of the amine versus acid of 0⋅25, 0⋅5, 0⋅75,
CHN calculated: C, 77⋅7%; H, 9⋅2%; N, 12⋅9%; 1⋅00, 1⋅25, 1⋅50, 2⋅00, 2⋅50 and 3⋅00 are obtained.
found: C, 77⋅7%; H, 9⋅3%; N, 12⋅8%; MS (LCMS): The change in the chemical shift values of the
C H N (m/z 433 (M + 1)
28 40 4
methine signal is plotted against the relative concen-
tration of the acid versus amine in a 400 MHz NMR
spectrometer.
1
2.4 H-NMR shift experiments
NMR shift experiments were performed on a
3. Results and discussion
400 MHz NMR spectrometer at 25°C by mixing the
compounds 1–5 with the acids 6–8 in varying ratios We have chosen the chiral diamines (1–2) and mac-
in CDCl , until maximum splitting of the signals rocyclic amines (3–5) to examine their chiral recog-
3
were observed.
2.4a Evaluation of stoichiometry of the complex
formed between 1 and (R)-and (S)-mandelic acid 6
by Job’s method: The stoichiometry of the com-
plex formed between 1 and 6 was determined
according to Job’s method of continuous variations.
Equimolar amounts of 1 (0⋅025 M) and (R) or (S)-6
(0⋅025 M) were prepared in CDCl (5 mL). These
3
solutions were distributed among ten NMR tubes in
such a way that the mole fractions of 1 and 6 in the
resulting solutions increased from 0⋅1 to 0⋅9. The
complexation induced shifts of the methine signal
(Δδ) were multiplied by the mole fraction of the acid
6 (X) and plotted against X to obtain the Job’s plot
(figure 2).
2.4b Evaluation of the stoichiometry of the com-
Figure 2. Job’s plot obtained for 1 and either (R) and
plex formed between 3 and (R)-and (S)-mandelic
(S)-mandelic acids 6 [X = mole fraction of the acid;
α
acid 6 by Job’s method: The stoichiometry of the
Δδ = change in the chemical shift of the C H proton
signal of (R)- and (S)-mandelic acid].
complex formed between 3 and 6 was determined

564
Mariappan Periasamy et al
nition ability towards mandelic acid 6 and 2,3- The macrocycle 4 was prepared by the methylation
22
diphenylsuccinic acid 7 and N-Ts-phenylglycine 8 of 3 using a mixture of formic acid and formalde-
1
by H-NMR spectroscopy. The chiral diamines 1 hyde (3).
and 2 were readily synthesized by reductive N-
alkylation of (R,R)-trans-1,2-diaminocyclohexane
with corresponding prochiral ketones in this labora-
20
tory (1).
(1)
(3)
23
The macrocycle 3 was synthesized following a
2
The macrocycle 5 was synthesized by NaBH /I
4
21
reported procedure via [3 + 3] cyclocondensation
reduction of insoluble mixture of the amides
of (R,R)-1,2-diaminocyclohexane with terephthal-
obtained by the reaction of (R,R)-1,2-diaminocyclo-
24
aldehyde and then reduction of the corresponding
hexane with isophthaloyl chloride (4). The mixture
macrocyclic hexaimine using NaBH /MeOH reagent
4
of the amines obtained after reduction was purified
by chromatography to obtain the macrocyclic amine
5 in pure form.
system (2).
(2)
(4)
25
The presence of the protonable amine groups would
lead to the formation of corresponding diastereo-
meric salt with chiral carboxylic acids. As a result,
the methine proton signal of the carboxylic acids
splits into two singlets. Initially, the easily accessed
chiral amines 1 and 2 were examined as chiral sol-
Figure 3. Job’s plot obtained for 3 and either (R)- and
(S)-mandelic acids 6 [X = mole fraction of the acid;
α
Δδ = change in the chemical shift of the C H proton sig-
Figure 4. Structures of the carboxylic acids (6–8) studied.
nal of (R)- and (S)-mandelic acid].

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids
565
1
Table 1. Measurement of H chemical shift non-equivalences (ΔΔδ) of the acids 6–8 in the pre-
1 a
sence of chiral acyclic amine receptor 1–2 by H NMR spectroscopy (400 MHz,) in CDCl .
3
Amine-1
Ratio of amine : acid
Amine-2
Ratio of amine : acid
Acid
Proton
ΔΔδ (Hz)
ΔΔδ (Hz)
α-H
α-H
α-H
1 : 3
1 : 1
53⋅6
69
1 : 2⋅3
48
55⋅2
28⋅6
2⋅9
1 : 2
118
3⋅2
CH (Ts)
3
1 : 3
1 : 3
NH
68⋅7
0⋅0
a
Typical conditions: concentration of the acid and the receptor is 100 mM in 0.5 mL of CDCl , and
3
the spectra are recorded at 25°C.
1
Table 2. Concentration variation of H NMR chemical
shift non-equvalence (ΔΔδ) of acid 6 in the presence of
receptor amine 1 with the mole ratio of 3 : 1.
Entry
Total molar conc. (mM)
ΔΔδ (Hz)
1
2
3
4
5
0⋅0025
5
18
20⋅4
37⋅6
41⋅2
53⋅6
15
25
100
Some interesting observations have been made
during these studies. First of all, the signals from the
acids move upfield (Δδ < 0), suggesting a deproto-
nation of carboxylic group. Only, the NH proton
from N-Ts-phenylglycine (8) resonates at lower field
upon the addition of receptor, which can be inter-
preted as formation of a stronger intramolecular hy-
drogen bond with the carboxylate anion thus
formed. Concomitantly, signals from the receptor
move downfield, which clearly indicates the proton
transfer from the acid to the receptor, leading to the
corresponding diastereomeric salts. These salts are
1 α
Figure 5. Partial H NMR spectra showing C H and
NH signals for racemic 8 (100 mM, CDCl , 400 MHz,
3
25°C) (a) in the absence and (b) in the presence of 0⋅33
equiv. of (R, R, R, R)-1.
vating agents towards mandelic acid 6, and 2,3-
diphenylsuccinic acid 7 and N-Ts-phenylglycine 8
1
by H-NMR spectroscopy (figure 4).
The experiments were carried out by adding in-
creasing amounts of solution of racemic acid (6–8)
in CDCl (100 mM) to a solution of chiral amine (1–
3
2) in CDCl (100 mM). Immediately after each addi-
3
1
tion, H NMR spectrum was acquired in a 400 MHz
expected to form intimate ionic pairs in CDCl , ren-
3
spectrometer at room temperature. The splitting val-
ues between proton signals corresponding to each
enantiomer of acids (6–8) (ΔΔδ) after addition of re-
ceptors (1–2) are summarized in table 1. In the pres-
ence of receptors 1 and/or 2, the chemical shift non-
equivalences of at least one of the protons of se-
lected acids are large enough to give base line reso-
lution on a 400 MHz NMR instrument at 25°C.
When the receptor 1 to N-Ts-phenylglycine 8 ratio
dering the observed anisochronic nuclei in NMR for
the corresponding enantiomers of acids.
According to the theory of chemical equilibrium,
upon increasing the concentration, the mole fraction
of the reactants decreases for a combination reaction.
So, it can be predicted that when the fractional
population of free acid is smaller the ΔΔδ is larger at
a larger concentration, which is in accordance with
the experiments (table 2) on the effect of concentra-
α
1
was 1 : 3, maximum non-equivalences of the C H
tion on the H chemical shift non-equivalences
proton (118 Hz) was obtained (figure 5).
(ΔΔδ) of the strong acid 6 in the presence of recep-

566
Mariappan Periasamy et al
tor 1. When the concentration decreased from amine (3–5) in CDCl (30 mM) to a solution of
3
100 mM to 0⋅0025 mM, the non-equivalent chemical racemic 2,3-diphenyl succinic acid 7. The splitting
α
shift is decreased by only 35⋅6 Hz, from 53⋅6 Hz to between methine proton (C H) signals correspond-
18 Hz.
To confirm the formation of multimolecular com- addition of receptors (3–5) have been shown in
plexes, Job’s plot analysis was performed for each table 3.
enantiomer of the acid 6 (figure 2) in separate For all tested examples, the signals for the protons
experiments, showing a clear 1 : 3 receptor:acid (C H) attached to the asymmetric carbon of the sub-
stoichiometry for both enantiomers of the acid with strate were split. In the case of enantiomeric recog-
receptor 1 as expected from the experimental data. nition of mandelic acid and 2,3-diphenylsuccinic
ing to each enantiomer of the acids (6–7) (ΔΔδ) after
α
Finally, we have examined the practical applica- acid by the macrocyclic amine 3 and 5, the baseline
bility of this method for the measurement of enanti- resolution was good enough for an accurate integra-
omeric excess of carboxylic acids. With this aim, tion whereas in the case of macrocyclic amine 4 the
samples containing different proportions of both the splitting of the methine proton signal was only 3-
enantiomers of 6 (100 mM in 5 mL CDCl ) were 4 Hz. The macrocycle 5 was also used to determine
3
1
prepared and analysed with H NMR method using the enantiomeric excess of non-racemic samples of
the receptor amine 1 (100 mM in 5 mL CDCl ) in 2,3-diphenylsuccinic acid. The difference in chemi-
3
1 : 3 receptor : acid molar ratio (figure 7). Integra- cal shift of the methine proton signals of racemic
α
1
tion of the corresponding C H H NMR signals mandelic acid 6 was found to be 17⋅6 Hz in the
show an excellent linear correlation of the observed presence of the macrocyclic amine 3 when the ratio
% ee’s with that of expected % ee’s based on HPLC of amine and acid was 1 : 3. However, in the case of
29
method.
Similarly, we have examined the chiral recogni- ence of 11⋅6 Hz was observed when the ratio of
tion ability of easily accessed chiral macrocyclic amine and acid was 6 : 1 (figure 6).
amines (3–5) towards mandelic acid 6 and 2,3- To confirm the formation of multimolecular
2,3-diphenylsuccinic acid 7, a chemical shift differ-
1
diphenylsuccinic acid 7 by H NMR spectroscopy. complexes, Job’s plot analysis was performed for
The experiments were carried out by adding increas- each enantiomer of acid 6 (figure 3) in separate
ing amounts of the solution of racemic mandelic experiments. A clear 1 : 3, receptor:acid stoichio-
acid 6 in CDCl (30 mM) to a solution of the chiral metry for both enantiomers of the acid was obseved.
3
macrocyclic amine (3–5) in CDCl (30 mM). Imme- These experiments also agree with a tri-protonation
3
1
diately after each addition, H NMR spectrum was state of the macrocycle 3 in optimal supramolecular
recorded in a 400 MHz spectrometer at 25°C. Dif- complexes. From the plot (figure 3), it is evident
ferent receptors (3–5) to acid 6 molar ratios were that the chemical shift changes of (S)-mandelic acid
analysed.
are greater when compared to the (R)-mandelic acid.
Similar experiments were carried out by varying In order to further assess the discriminating ability
the amounts of solution of the chiral macrocyclic of the amine 3, the titration of the macrocyclic
amine 3 with the (R) and (S)-mandelic acids was
carried out by varying the relative ratio of the amine
and acid as 0⋅25, 0⋅5, 0⋅75, 1⋅00, 1⋅25, 1⋅5, 2⋅00, 2⋅5
and 3⋅00 and the change in chemical shift of the
methine signal of the (R) or (S)-mandelic acid was
recorded. The relative concentration of the amine
(C) was plotted against the change in chemical shift
of the methine signal (ΔΔδ) (figure 8).
The splitting of the methine proton signal of the
2,3-diphenylsuccinic acid 7 was found to be good
enough (40 Hz) when the macrocyclic amine 5 was
1 α
Figure 6. Partial H NMR spectra showing C H signal
used in 2 : 1 ratio with the diacid 7. In order to
evaluate the efficiency of the amine 5 in the deter-
mination of the enantiomeric excess of the diacid 7,
the enantiomeric composition of the non-racemic
for racemic acids 6 and 7 (30 mM, CDCl , 400 MHz,
3
25°C) (a) in the presence of macrocyclic amine
3 (0⋅33 equiv. of 30 mM, CDCl ) (b) in the presence of
3
macrocyclic amine 3 (6 equiv. of 30 mM, CDCl ).
3

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids
567
1
Figure 7. Selected region of the H NMR (400 MHz) spectra of 6 (100 mM)
with various enantiomeric purities in the presence of (1R, 2R, 1′R, 1″R)-1
(100 mM) in CDCl at 25°C. The %ee values were obtained from the integration
3
of the signals and the %ee values obtained by HPLC analysis are given in paren-
theses.
1
Table 3. Measurements of H NMR chemical shift non-equivalences (ΔΔδ, 400 MHz) of
α
methine proton (C H) signals of the acids 6 and 7 in the presence of the macrocyclic amines 3, 4
o
and 5 in CDCl (30 mM) at 25 C.
3
ΔΔδ
ppm
ΔΔδ
Macrocyclic
amine
Ratio of
Ratio of
Entry
amine : acid
Hz
amine : acid
ppm
Hz
1
2
3
3
4
5
1 : 3
1 : 6
1 : 4
0⋅044
0⋅011
0⋅034
17⋅6
4⋅4
6 : 1
1 : 2
2 : 1
0⋅029
0⋅009
0⋅100
11⋅6
3⋅6
13⋅6
40⋅0
samples of the diacid was determined in the pres- the ee values measured by optical rotation (figure 9).
ence of the macrocyclic amine. It was observed that the methine proton signal of the
The non-racemic samples of the diacid 7 were (S,S)-7 was shifted more downfield compared to the
obtained by partial resolution using (S)-proline fol- (R,R)-7. In the presence of the macrocyclic amine 4
lowing a procedure reported from this laboratory to the splitting of the mandelic acid 6 was 4⋅4 Hz and
obtain the diacid with 71% ee from the precipitate that of 2,3-diphenylsuccinic acid 7 was 3⋅6 Hz.
26
fraction and with 17% ee from the filtrate fraction.
Optimum results were obtained when the ratio of the
The enantiomeric excess of the non-racemic diacid 7 macrocyclic amine 3 and mandelic acid was 1 : 3 and
1
with 71% ee and 17% ee determined by H-NMR in that of the amine 3 and 2,3-diphenylsuccinic acid
the presence of the amine 5 was in agreement with was 6 : 1. In the case of the macrocycle 5, better

568
Mariappan Periasamy et al
results were obtained when the ratio of 5 and of the enantiomeric purity of carboxylic acids (6–8).
mandelic acid was 1 : 4 and that of 5 and 2,3- The studies indicate that most of these compounds
diphenylsuccinic acid was 2 : 1 (table 3).
act as polytopic receptors, binding up to three mole-
cules of the substrate. Good splitting of the signals
was observed after addition of small amounts of the
receptor (CSA). The high symmetry and simple
4. Conclusion
1
H NMR spectrum of these CSA compounds reduce
Chiral trans-1,2-diaminocyclohexane derivatives 1–
5 were found to be useful as efficient chiral solvat-
ing agents (CSA) for the fast and easy determination
the possibility of large overlapping with signals of
the substrate. The formation of diastereomeric com-
plexes is fast and quantitative being possible its in
situ analysis by a 400 MHz spectrometer at room
temperature. Moreover, as the interaction between
receptor and substrate is non-covalent and pH-
dependent, both compounds can be separated and
recovered by a simple acid–base extraction proce-
dure. The easy accessibility of the chiral receptors
(1–5) from commercially available 1,2-diamino-
cyclohexane should make this methodology very
attractive for practical application as chiral solvating
agents (CSA) for carboxylic acids.
Acknowledgements
We thank University Grants Commission (UGC) for
support under the University with Potential for
Excellence (UPE), Centre for Advanced Study
(CAS-SAP) and UGC-MHRD Chemistry Network-
ing Centre programmes. Support of the Department
of Science and Technology (DST) under Fund for
Improvement of Science and Technology Infrastruc-
ture in Universities (FIST) programme and award of
the DST-JC Bose National Fellowship grant to MP
are gratefully acknowledged. MD is thankful to the
Council of Scientific and Industrial Research (CSIR)
for research fellowship.
1
Figure 8. H-NMR titration curves of 3 with (R)- and
(S)-mandelic acids 6 [C = relative concentration of the
amine with respect to the acid; ΔΔδ = change in the
chemical shift of the methine proton of 6].
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CDCl at 25°C. The %ee values given are obtained from
3
integration of the signals and the average %ee values ob-
tained by graphical analysis of the signals after expansion
(100%, 200%) are given in parentheses.

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids
569
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