Salts of (+)-deoxycholic acid with amines: Structure, thermal stability, kinetics of salt formation, decomposition and chiral resolution

Article abstract of DOI:10.1039/c2ce26706c

(+)-Deoxycholic acid forms salts with 1-propylamine, di-n-butylamine, sec-butylamine and 3-methyl-2-butylamine. The salts were characterised using thermal analysis and single crystal X-ray diffraction. The chiral discrimination of (+)-deoxycholic acid for racemic sec-butylamine and racemic 3-methyl-2-butylamine was studied and correlated with the structural and thermal results. A mixture of (+)-deoxycholic acid and racemic sec-butylamine yielded crystals of (R)-2-butylammonium deoxycholate. (+)-Deoxycholic acid was exposed to vapours of propylamine and racemic sec-butylamine and the kinetics of absorption were determined. The kinetics of decomposition of powdered samples obtained from (+)-deoxycholic acid with di-n-butylamine and racemic sec-butylamine were investigated. Crystallisation of (+)-deoxycholic acid with racemic 3-methyl-2-butylamine resulted in crystals of (S)-3-methyl-2- butylammonium deoxycholate.

Full text of DOI:10.1039/c2ce26706c

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Salts of (+)-deoxycholic acid with amines: structure,
thermal stability, kinetics of salt formation,
decomposition and chiral resolution3
Cite this: CrystEngComm, 2013, 15,
931
´
Ayesha Jacobs,* Nikoletta B. Bathori, Luigi R. Nassimbeni and Baganetsi K. Sebogisi
(+)-Deoxycholic acid forms salts with 1-propylamine, di-n-butylamine, sec-butylamine and 3-methyl-2-
butylamine. The salts were characterised using thermal analysis and single crystal X-ray diffraction. The
chiral discrimination of (+)-deoxycholic acid for racemic sec-butylamine and racemic 3-methyl-2-
butylamine was studied and correlated with the structural and thermal results. A mixture of (+)-
deoxycholic acid and racemic sec-butylamine yielded crystals of (R)-2-butylammonium deoxycholate. (+)-
Deoxycholic acid was exposed to vapours of propylamine and racemic sec-butylamine and the kinetics of
absorption were determined. The kinetics of decomposition of powdered samples obtained from (+)-
deoxycholic acid with di-n-butylamine and racemic sec-butylamine were investigated. Crystallisation of (+)-
deoxycholic acid with racemic 3-methyl-2-butylamine resulted in crystals of (S)-3-methyl-2-butylammo-
nium deoxycholate.
Received 15th June 2012,
Accepted 7th November 2012
DOI: 10.1039/c2ce26706c
www.rsc.org/crystengcomm
resolution of erythro-2,3-bis(p-methoxyphenyl)butyl- and pen-
tyl-amines7 as well as trans-3-amino-4-hydroxycyclopentene.8
Introduction
(+)-Deoxycholic acid, H, is one of the important bile acids
whose general formula, based on the steroid nucleus, is shown
in Fig. 1, which also names some important bile acids and
their substituents R1–R4 (Table 1).
Crystallisation of
H with racemic camphorquinone and
racemic endo-(+)-3-bromocamphor yielded crystals of the (S)-
enantiomers together with crystals of the racemic guests.9
The amine salts of H, however, have not been studied. In
this work we have analysed the structures and thermal
characteristics of the salts formed by H with the achiral guests
Many of these acids form crystalline inclusion compounds
with a variety of guests and these cholic acids have been the
subject of intense structural studies since the 1930’s.
Deoxycholic acid (H) is dextro-rotatory, [a]2D0 + 55u in ethanol.1
Giglio2 has reviewed the inclusion compounds of H, their
structures, lattice energies and the enthalpy changes of the
guest-release reactions. Miyata3,4 lists forty bile acids and their
derivatives, discusses their polymorphic forms, their dynamic
behaviour and reactions occurring in their channel structures.
The bile acids have a rigid skeleton and their shape is
characterised by a cis-fusion of the A and B rings, while the B,
C and D rings are trans-fused. Hydroxyl groups point below the
steroidal plane giving a hydrophilic face, while two methyl
groups point above the plane, forming a lipophilic face. The
side chain containing the carboxylic moiety, is flexible. All the
bile acids are chiral and have been employed to resolve
racemic modifications.5 Recently lithocholic acid was
employed to resolve sec-butylamine.6 H was used in the
1-propylamine (PPA) and di-n-butylamine (DBA).
H was
exposed to varying vapour pressures of the guests 1-propyla-
mine and racemic sec-butylamine, respectively, and the
kinetics of guest absorption were analysed. The kinetics of
decomposition of the salts formed by H with di-n-butylamine
and racemic sec-butylamine were also determined. Chiral
resolution via diastereomeric salt formation remains an
important topic in chemistry,10 however, the mechanism of
chiral selectivity remains poorly understood. In view of this we
Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of
Technology, PO Box 652, Cape Town 8000, South Africa.
E-mail: jacobsa@cput.ac.za; Fax: +27 21 460 3854; Tel: +27 21 460 3167
Electronic supplementary information (ESI) available: Hydrogen bond data
3
available for all salts. CCDC 886458–886464. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ce26706c
Fig. 1 General steroid structure.
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(H2)(R-BA+) was obtained by slow evaporation of a saturated
solution of H in racemic sec-butylamine.
Table 1 Important bile acids
(H2)(S-BA+) was obtained by slow evaporation of a saturated
solution of H in (S)-sec-butylamine.
R1
R2
R3
R4
Name
OH
OH
OH
OH
OH
OH
OH
OH
H
OH
H
OH
H
OH
H
H
H
OH
OH
H
H
OH
OH
COOH
COOH
COOH
COOH
CH2COOH
CH2COOH
CH2COOH
CH2COOH
Norlithocholic acid
Norchenodeoxycholic acid
Nordeoxycholic acid
Norcholic acid
(H2)(R-MBA+) and (H2)(S-MBA+): Powdered samples were
obtained from slow evaporation of saturated solutions of H in
the respective amine. These powders were dissolved in acetone
and suitable crystals were obtained via slow evaporation.
Lithocholic acid
Chenodeoxycholic acid
Deoxycholic acid (H)
Cholic acid
Structure analysis
OH
Unit cell dimensions were determined from intensity data
measured on Kappa CCD11 and Bruker DUO APEX II12
diffractometers using graphite-monochromated Mo Ka radia-
tion. The intensity data were collected by the standard phi
scan and omega scan techniques, scaled and reduced using
DENZO-SMN13 or SAINT-Plus.14 All of the structures were
solved using direct methods and refined by full-matrix least
squares with SHELX-97,15 refining on F2. X-Seed16 was used as
a graphical interface. For all the structures the non-hydrogen
atoms were located in difference electron density maps. The
hydrogens of the host and guests not involved in hydrogen
bonding were placed with geometric constraints and allowed
to refine isotropically. The hydroxyl hydrogens of the host and
the hydrogens attached to the nitrogen of the guests were
found in the electron density map and allowed to refine
isotropically. Friedel pairs were merged for the final refine-
ment. The crystal data results are summarised in Tables 2 and
3.
have studied the chiral discrimination of H for racemic sec-
butylamine (BA) and racemic 3-methyl-2-butylamine (MBA).
The chiral resolution results of the two systems were
correlated with the structures and thermal parameters in an
effort to gain further insight into the resolution process. The
atomic numbering scheme for the host and the diagram of the
guests is given in Scheme 1.
Experimental section
Crystal growth
(H2)(PPA+)?ACE: H was ground with a few drops of 1-propy-
lamine. The powdered sample was dissolved in AR grade
acetone (ACE) that had been dried using molecular sieves. The
saturated solution yielded suitable crystals via slow evapora-
tion.
Thermal analysis and kinetics
(2H2)(2PPA+)?4.3H2O was obtained in a similar manner
except the powdered sample was dissolved in undried acetone.
(H2)(DBA+) was obtained by grinding samples of H and
drops of di-n-butylamine. The powder was dissolved in acetone
and crystals were obtained through slow evaporation of the
solution.
Thermogravimetric analysis (TG) and differential scanning
calorimetry (DSC) were performed on a Perkin Elmer 6 series
system using a purge gas of nitrogen at 20 mL min21
.
Experiments were conducted between 303–700 K at a heating
rate of 10 K min21. The crystals were removed from the mother
liquor, dried on filter paper and crushed prior to analysis.
Kinetics of absorption: this was carried out with the aid of a
special device, in which the powdered host compound is
placed on an analytical balance and is enclosed in a chamber
containing the volatile liquid guest and its vapours. The
system is thermostated and the increase in mass with time was
automatically recorded on a computer. The apparatus has
been described in detail.17 The vapour pressure of the amine
was varied by preparing solutions of known mol fractions of
the amine and water. A separate experiment confirmed that H
does not absorb water. Ideal behaviour of the amine–water
mixtures was assumed. The mass gain at 25 uC was recorded
using ALPHATIME software.
Kinetics of desorption: non-isothermal kinetics18,19 was
performed on powdered samples formed directly from
dissolution of H in the appropriate amine.
Results and discussion
Salts of achiral amines: structures
For all the structures proton transfer is observed from the
Scheme 1 Atomic labelling scheme for host and schematic diagram of guests.
932 | CrystEngComm, 2013, 15, 931–939
carboxylic moiety of H to the nitrogen of the amine guest,
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Table 2 Crystal data parameters (salts of achiral guests) H = C24H40O4
Compound
(H2)(PPA+)?ACE
(2H2)(2PPA+)?4.3H2O
(H2)(DBA+)
Structural formula
(H2)(C3H10N+)?C3H6O
509.75
(2H2)(2 C3H10N+)?4.3H2O
980.47
(H2)(C8H20N+)
521.8
Molecular mass (g mol21
)
Data collection temp. (K)
173(2)
Monoclinic
P21
11.0361(11)
7.7101(7)
17.9654(18)
90.00
105.750(2)
90.00
1471.3(2)
173(2)
Triclinic
P1
7.7287(6)
11.5210(9)
16.5589(13)
81.143(2)
79.051(2)
89.485(2)
1430.03(19)
1
1.138
0.079
542.7
173(2)
Monoclinic
P21
14.043(3)
7.8258(16)
14.055(3)
90.00
100.94(3)
90.00
1516.5(5)
2
1.143
0.073
580
Crystal system
Space group
a (Å)
b (Å)
c (Å)
a (u)
b (u)
c (u)
Volume (Å3)
Z
2
Dc, Calc density (g cm23
)
1.151
0.076
564
Absorption coefficient (mm21
F(000)
)
h range
Limiting indices
1.92–28.31
214, 13; ¡10; ¡23
13 768/3922
1.022
R1 = 0.0408; wR2= 0.0950
R1 = 0.0554; wR2 = 0.1023
0.274; 20.203
2.03–28.38
¡10; 215, 12; 216, 22
11 575/7136
1.032
R1 = 0.0442; wR2 = 0.1070
R1 = 0.0543; wR2= 0.1134
0.308; 20.191
1.48–28.29
¡18; ¡10; ¡18
7058/4023
1.030
R1 = 0.0413; wR2 = 0.0941
R1 = 0.0633; wR2 = 0.1028
0.235; 20.198
Reflections collected/unique
Goodness-of-fit on F2
Final R indices [I . 2s(I)]
R indices (all data)
Largest diff. peak and hole (e Å23
)
forming salts. This is a classic interaction dependent on the
difference in pKa between the acid and the base.20
For (2H2)(2PPA+)?4.3H2O the presence of water molecules
results in extensive hydrogen bonding as can be seen in Fig. 4.
The asymmetric unit contains two host molecules and two
guest molecules, one of which is disordered. In addition, water
molecules maintain a bridging role connecting neighbouring
host molecules as well as linking H and PPA molecules to form
a continuous network. The packing is shown in Fig. 5. This
again displays double layers of the host where the lipophilic
faces alternate with the hydrophilic faces. The water and
amine guests bridge alternative hydrophilic layers of the host.
The hydrogen bonding found in (H2)(PPA+)?ACE is shown in
Fig. 2 and can be described with the graph set21 N1 = R54(12). It
forms an infinite network running along the [010] direction.
Fig. 3 shows the packing of the structure viewed along b. It is
characterised by alternate layers of the host and the amine/
acetone molecules. The amine cation is disordered, the major
component refined with a site occupancy factor of 0.813. The
acetone molecules are not involved in hydrogen bonding.
Table 3 Crystal data (salts of chiral guests) H = C24H40O4
Compound
(H2)(R-BA+)
(H2)(S-BA+)
(H2)(R-MBA+)
(H2)(S-MBA+)
Structural formula
(H2)(C4H12N+)
465.70
(H2)(C4H12N+)
465.70
(H2)(C5H14N+)
479.72
(H2)(C5H14N+)
479.72
Molecular mass (g mol21
)
Data collection temp. (K)
173(2)
Monoclinic
C2
23.511(4)
7.6318(12)
18.196(3)
90.00
123.03(2)
90.00
2737.3(10)
4
1.130
0.074
1032
173(2)
Monoclinic
P21
10.1547(11)
7.5678(8)
17.645(2)
90.00
90.915(3)
90.00
1355.8(5)
2
1.141
0.074
516
296 (2)
Monoclinic
P21
11.501(2)
7.7042(15)
17.175(3)
90.00
106.19(3)
90.00
1461.5(5)
2
1.090
0.071
532
173(2)
Monoclinic
P21
11.026(2)
7.5245(15)
17.600(4)
90.00
105.26(3)
90.00
1408.7(5)
2
1.131
0.073
532
Crystal system
Space group
a (Å)
b (Å)
c (Å)
a (u)
b (u)
c (u)
Volume (Å3)
Z
Dc, Calc density (g cm23
)
Absorption coefficient (mm21
F(000)
)
h range
Limiting indices
1.74–26.39
¡29; ¡9; ¡22
10 356/3026
1.050
2.01–28.32
¡13; ¡10; ¡23
12 140/3604
1.024
1.84–25.63
214, 12; ¡9; ¡20
8347/5311
1.006
2.51–25.30
¡13; ¡9; ¡21
5015/2760
0.964
Reflections collected/unique
Goodness-of-fit on F2
Final R indices [I . 2s(I)]
R indices (all data)
R1 = 0.0462; wR2 = 0.1115 R1 = 0.0403; wR2 = 0.0986 R1 = 0.0494; wR2 = 0.1192 R1 = 0.0425; wR2 = 0.0869
R1 = 0.0663; wR2 = 0.1222 R1 = 0.0492; wR2 = 0.1046 R1 = 0.0869; wR2 = 0.1380 R1 = 0.0938; wR2 = 0.0989
0.364; 20.214
Largest diff. peak and hole (e Å23
)
0.275; 20.171
0.199; 20.139
0.182; 20.183
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Fig. 6 Hydrogen bonding in (H2)(DBA+).
Fig. 2 Hydrogen bonding in (H2)(PPA+)?ACE.
Fig. 7 Hydrogen bonding in (H2)(R-BA+).
Fig. 3 Packing diagram of (H2)(PPA+)?ACE viewed down [010].
structure. The compound crystallises in the space group C2
with Z = 4. The structure is stabilised by extensive hydrogen
bonding and each N–H moiety of the amine ion acts as a donor
either to a carboxylate oxygen or the hydroxyl oxygen of the
host. This is shown in Fig. 7, which displays the ring nature of
the hydrogen bonding scheme R45(12).
For the (H2)(DBA+) structure, bifurcated hydrogen bonds
connect two hosts to a DBA molecule. These repeating units
+
are linked via (Host)COO2 (DBA)HN H 2OOC(Host) hydro-
gen bonds which extend in an infinite chain along the [010]
direction (Fig. 6). The DBA guests occupy voids in the (110)
plane. The hydrogen bond results for all the structures have
…
…
The compound (H2)(S-BA+) was crystallised directly from
pure S-BA in the space group P21 with Z = 2. The hydrogen
bonding of this compound is analogous to that of its R-BA
analogue. The crystal data for these compounds is given in
Table 3. The packing of the two structures is different.
Whereas pairs of H2 anions are related in their lipophilic
faces by a diad screw axis in both structures, the lipophobic
been tabulated in the ESI.
3
Salts of chiral amines: structures
Crystals of (H2)(R-BA+) were obtained from a solution of the
acid in racemic sec-butylamine. Thus, this resolution was
successful in that no evidence of S-BA+ was found in the crystal
Fig. 4 Hydrogen bonding in (2H2)(2PPA+)?4.3H2O.
Fig. 5 Packing diagram of (2H2)(2PPA+)?4.3H2O viwed down [100].
934 | CrystEngComm, 2013, 15, 931–939
Fig. 8 Packing diagram of (a) (H2)(R-BA+) and (b) (H2)(S-BA+).
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Fig. 10 Packing diagrams of (H2)(S-MBA+) in blue and (H2)(R-MBA+) in red,
Fig. 9 Hydrogen bonding in (H2)(R-MBA+).
overlaid.
faces are related by a diad in the (H2)(R-BA+) structure (Fig. 8a)
but by a two-fold screw axis in the (H2)(S-BA+) structure
(Fig. 8b). This results in a relative shift of the hydrophobic
faces of the host anions.
Both (H2)(R-MBA+) and (H2)(S-MBA+) crystallised in the
space group P21 with Z = 2. The data collection for the R-MBA
compound was conducted at room temperature due to the
crystal fracturing at low temperatures. A racemic mixture of
MBA with the host resulted in the (S)-enantiomer being
Fig. 11 Hirshfeld plots for a. (H2)(R-BA+), b. (H2)(S-BA+), c. (H2)(R-MBA+) and d. (H2)(S-MBA+).
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Table 4 Hydrogen bonding (salts of chiral guests)
Compound
(H2)(R-BA+)
(H2)(S-BA+)
(H2)(R-MBA+)
(H2)(S-MBA+)
…
N1G O3
2.890(3)
2.752(3)
2.785(3)
3.261(3)
2.821(2)
3.289(2)
2.730(2)
2.785(2)
2.878(3)
2.990(4)
2.738(4)
2.999(4)
2.831(3)
3.303(3)
2.724(3)
2.763(3)
…
N1G O24A
a
…
N1G O24A
…
N1G O24B
a
:symmetry generated atom
+
chosen. For (H2)(R-MBA+) the NH3 group acts a donor with
each N–H bond involved in hydrogen bonding to either the
carboxyl or hydroxyl functionality of neighbouring host
molecules. Bifurcated bonds are also formed between the
Interestingly, a grinding experiment whereby a few drops of
racemic sec-butylamine was added to H (ground for a few
minutes) resulted in the kinetically preferred (H2)(S-BA+). This
is in contrast to the thermodynamically stable product
(H2)(R-BA+) obtained upon slow stirring a 1 : 1 mixture of H
and racemic sec-butylamine, which is identical to that
obtained by slow evaporation of the solution that yielded
single crystals. The powder X-ray diffraction results are shown
in Fig. 12. An analogous experiment could not be carried out
with racemic 3-methyl-2-butylamine due to the similarity
between the calculated powder patterns23 of (H2)(R-MBA+)
and (H2)(S-MBA+).
COO2 of the host and the NH3 group of the amine. This can
be described by the graph set R35(10)R12(4). The hydrogen
bonding is shown in Fig. 9.
+
The hydrogen bonding in the (H2)(S-MBA+) compound is
analogous to that found in the R-MBA+ structure. The packing
diagrams for both structures have been overlaid to illustrate
their similarity (Fig. 10).
Resolution results
Thermal analysis and kinetics
The salient point of the resolution experiment results is that
the host, H, preferentially selects (R)-sec-butylamine (BA) or (S)-
3-methyl-2-butylamine (MBA) from their respective racemic
modifications. We therefore analysed the non-bonded inter-
actions that impinge on each guest in the four structures. In
order to be self consistent, the final refinements were carried
out treating the –CH3 and –NH3+ moieties as rigid groups with
normalised d(C–H) and d(N–H) distances set at 1.08 Å. We
employed the program Crystal Explorer, which calculates the
Hirshfeld surfaces of a molecule in a crystal structure and
depicts all the molecular interactions of the targeted molecule
with its neighbours in the form of fingerprint plots.22
The results of the TG and DSC analyses are summarised in
Tables 5 and 6. For the decomposition of (H2)(PPA+)?ACE the
mass loss observed is due to the release of the PPA guest
(calculated 13.1%). The acetone evaporated prior to analysis.
This is in accordance with the structural results where the
acetone occupies channels and is not involved in hydrogen
bonding. A single broad endotherm corresponds to guest loss
and concomitant host melt.
For (2H2)(2PPA+)?4.3H2O the loss of water is followed by the
release of PPA (total calculated 20.0%) and the host melt. This
is depicted by three endotherms in the DSC. The loss of DBA in
(H2)(DBA+) is shown by a single mass loss step in the TG.
A complex endotherm in the DSC curve is due to the release
of DBA and the host melt. For all three structures decomposi-
tion was observed after 600 K. The endotherm associated with
The results are shown in Fig. 11, which displays the
fingerprint plots for each guest. The top row displays the
maps of the complete set of interactions. In the second and
third rows we highlight the close contacts where the sum of
the internal and external distances are ¡2.8 Å. When
comparing the (H2)(R-BA+) and (H2)(S-BA+) structures we
note that the hydrogen bonds are very similar (Table 4): there
are two strong hydrogen bonds and one weaker one in both
structures. These are shown as spikes labelled 1 in Fig. 11a2
…
and b2. However, the H H contacts of the guests shown in
Fig. 11a3 and b3 and labelled 2, show significant differences.
2
+
…
Fig. 11a3, for (H )(R-BA ), shows more H H interactions
peaking at (de + di) = 1.11 + 0.90 = 2.01 Å, while Fig. 11b3
shows this interaction as 1.21 + 1.25 = 2.25 Å. This confirms a
closer fit of the carbon-bound hydrogens of the R-BA+ guest
with the surrounding host surface. This feature is even more
pronounced in the case of the (H2)(R-MBA+) and (H2)(S-MBA+)
structures. We again have similar O2 H–N hydrogen bonds
…
+
(Table 4), displayed as spikes labelled 1 in Fig. 11c2 and d2,
…
but the H H interactions are strongly different. In Fig. 11d3,
the peak labelled 2 occurs at (de + di) = 1.56 Å, much closer
than that in Fig. 11c3 at 1.95 Å.
Fig. 12 PXRD patterns of (a) (H2)(R-BA+) obtained from stirring, (b) calculated
(H2)(R-BA+), (c) calculated (H2)(S-BA+) and (d) (H2)(S-BA+) obtained from
grinding.
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Table 5 Thermal analysis results (salts of achiral guests)
Compound
(H2)(PPA+)?ACE
(2H2)(2PPA+)?4.3H2O
(H2)(DBA+)
H : G ratio
1 : 1 : 1
13.1
11.9
400–480
—
2 : 2 : 4.3
20.0
18.8
330–410 (H2O)
410–480 (PPA)
1 : 1
24.8
25.7
380–480
—
TG (calc % mass loss)
TG (exp % mass loss)
DSC endotherm range (T/K)
Table 6 Thermal analysis data (salts of chiral guests)
Compound
(H2)(R-BA+)
(H2)(S-BA+)
(H2)(R-MBA+)
(H2)(S-MBA+)
H : G ratio
1 : 1
15.7
15.7
1 : 1
15.7
15.3
395–509
1 : 1
18.4
17.8
405–495
1 : 1
18.4
17.8
412–503
TG (calc % mass loss)
TG (exp % mass loss)
DSC endotherm range (T/K)
406–478
the loss of the BA guest and the concomitant dissolution of the
host is diffuse. We note that the onset temperature for
(H2)(R-BA+) is 406 K, which is 11 K higher than that of the
(H2)(S-BA+) analogue. This is a measure of the higher stability
of the former compound and serves as an indication of why
the R-enantiomer is selected by the host from the racemic
amine than the stoichiometrically calculated amounts. The
resultant curves were linear after the absorption of the
stoichiometrically expected amount of amine. The linear curve
is indicative of a zero order reaction and in this example is
dependent on the surface area of the salt exposed to the amine
vapour. The curves were analysed until the end of the expected
mass gain with a molar ratio of 1 : 1 (H : amine). The mass
gain data were converted to the extent of the reaction:
modification.
A similar thermal profile was found for
(H2)(R-MBA+) and (H2)(S-MBA+) as illustrated in Fig. 13. The
higher onset temperature for the S-MBA+ compound illustrates
the greater stability of (H2)(S-MBA+).
mt{m0
a~
m?{m0
Kinetics of salt formation
where m0, mt and m‘ are the recorded masses at the start, during
and at the end of the experiment.
The rate of the reaction can be described by:
Kinetics of absorption were performed with the guests PPA
and racemic BA. Experiments were conducted at 298 K with
varying vapour pressure as described above. The resultant salts
formed were hygroscopic and absorbed greater quantities of
da
~kobsf (a)
dt
where kobs is the observed rate constant. Several models for the
kinetics are applicable and are based on various assumptions:
nucleation, geometrical contraction, diffusion and reaction order.
In the case of the reaction under study, the deceleratory geometric
model R2 (contracting area):
[1 2 (1 2 a)2] = kobs
t
Table 7 Kinetics of absorption results
Amine
PPA
Xamine
Pamine/mmHg
Slope kobs/min21
R
1
0.5
0.30
0.25
0.17
310.0
155.0
93.9
77.5
51.6
1.460
0.750
0.504
0.436
0.327
0.9914
0.9984
0.9966
0.9904
0.9979
Racemic BA
1
0.5
0.30
0.25
0.17
178
0.519
0.217
0.183
0.164
0.086
0.9953
0.9920
0.9951
0.9970
0.9992
89.0
53.4
44.5
29.7
Fig. 13 TG and DSC profiles for (a) (H2)(R-MBA+) and (b) (H2)(S-MBA+).
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completed at heating rates 2, 4, 10 and 32 K min21. The
resultant % mass loss vs. temperature curves were converted
into a vs. temperature curves. The data was analysed in the
range a = 0.3–0.7. Plots of logb vs. 1/T where b is the heating
rate are given in Fig. 15.
The activation energies were calculated using the relation-
ship
Ea
slope~{0:457
R
For H2BA+ the activation energy range was 201.6–250.1 kJ
mol21 and for H2DBA+ the activation energy was calculated as
101.9–116.4 kJ mol21
.
Fig. 14 Plot of kobs vs. Pamine where the blue diamonds indicate the absorption
Conclusion
of racemic BA.
(+)-Deoxycholic acid forms salts with the achiral and chiral
amines studied, via proton transfer from the carboxylic moiety
of the host to the nitrogen of the amine guest. We achieved
diastereomeric resolution of racemic mixtures of sec-butyla-
mine and 3-methyl-2-butylamine. Crystallisation of racemic
sec-butylamine and (+)-deoxycholic acid gave the (R)-enantio-
mer in the crystal structure. An analogous experiment with
racemic 3-methyl-2-butylamine yielded exclusively crystals
containing the (S)-enantiomer. The structures obtained from
crystallisation of (+)-deoxycholic acid in (R)-sec-butylamine and
(S)-sec-butylamine, respectively, were analysed and indicated
similar hydrogen bonding patterns but significant differences
…
in the H H interactions. A similar result was seen for
experiments with 3-methyl-2-butylamine. We have thus suc-
cessfully correlated the resolution results with the non-bonded
interactions in the crystal structures. The sensitivity of the
chiral discrimination process is further demonstrated by the
grinding experiment of (+)-deoxycholic acid and racemic sec-
butylamine where the (S)-sec-butylamine was selected, indicat-
ing the importance of reaction conditions on the resolution.
Fig. 15 Logb vs. 1/T plot for the decomposition of (a) H2BA+ and (b) H2DBA+.
Acknowledgements
We thank the Cape Peninsula University of Technology for
funding.
fitted all the data (a = 0.05–0.75 for PPA and a = 0.05–0.90 for BA).
The kobs values clearly depend on the vapour pressure of the
amine which was controlled by diluting to various mole fractions
with water. The results are given in Table 7.
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