Rational approach to the selection of conditions for diastereomeric ...
Rational approach to the selection of conditions for diastereomeric ...
Rational approach to the selection of conditions for diastereomeric ...
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1340 F. C. Ferreira et al. / Tetrahedron: Asymmetry 17 (2006) 1337–1348<br />
salt <strong>for</strong>mation (C > 1.5), but suggest that it is not so important<br />
<strong>for</strong> <strong>the</strong> region where neutral salt <strong>for</strong>mation takes place<br />
(C < 0.5). To follow this fur<strong>the</strong>r, specific calculations <strong>for</strong><br />
PEA and PPI2 are made in Figure 2c and d. Accounting<br />
<strong>for</strong>, or neglecting, acid–base equilibria does not affect <strong>the</strong><br />
predicted ee’s <strong>for</strong> a resolution based on <strong>the</strong> preferential precipitation<br />
<strong>of</strong> one <strong>of</strong> <strong>the</strong> neutral salts, as shown in Figure 2c<br />
<strong>for</strong> <strong>the</strong> case <strong>of</strong> PEA. However, considerably different ee’s<br />
are predicted by <strong>the</strong> different models (Fig. 2d) <strong>for</strong> <strong>the</strong> case<br />
<strong>of</strong> PPI2, where resolution is based on <strong>the</strong> difference in solubilities<br />
<strong>of</strong> <strong>the</strong> acidic <strong>diastereomeric</strong> salts. Consequently, it<br />
is concluded that <strong>the</strong> acid–base equilibrium <strong>of</strong> racemic<br />
amine and resolving diacid agent should be taken in<strong>to</strong> account,<br />
and from here onwards, model II will be employed<br />
in all calculations.<br />
Resolutions <strong>of</strong> both amines were per<strong>for</strong>med according <strong>to</strong><br />
<strong>the</strong> resolution pro<strong>to</strong>cols described at constant racemic<br />
amine concentrations, with varying amounts <strong>of</strong> resolving<br />
agent added <strong>to</strong> vary C. For both systems, <strong>the</strong> ee’s <strong>of</strong> both<br />
solid and mo<strong>the</strong>r liquor was measured, as well as <strong>the</strong> Y<br />
and mo<strong>the</strong>r liquor pH. The experimental and calculated<br />
results obtained are plotted in Figure 3a–d. These show<br />
a good relationship between predicted and experimentally<br />
measured values. Figure 3a shows a good match between<br />
ee <strong>for</strong> PEA except at C < 0.5; Figure 3c shows that <strong>for</strong><br />
PPI2, ee is well-predicted across <strong>the</strong> range <strong>of</strong> C, while<br />
Figure 3b and d shows that <strong>the</strong> model predictions <strong>for</strong> Y<br />
and pH both compare very well with <strong>the</strong> experiment <strong>for</strong><br />
both amines.<br />
PPI2 resolutions were per<strong>for</strong>med in ace<strong>to</strong>ne–water<br />
97:3 wt % at 5 °C with amine concentrations <strong>of</strong> 280 mM.<br />
The maximum ee <strong>for</strong> <strong>the</strong>se resolutions were found <strong>for</strong><br />
C > 1.5. Under <strong>the</strong>se <strong>conditions</strong>, (R)-acidic salt was <strong>for</strong>med<br />
at concentrations (140 mM) lower than its solubility limit<br />
(Ks AR = 361 mM) and so it remains completely dissolved<br />
in <strong>the</strong> mo<strong>the</strong>r liquor. The (S)-acidic salt has a low solubility<br />
limit (Ks AS = 12 mM), and hence, precipitation was observed.<br />
For 0.2 < C < 0.75, <strong>the</strong> (R)-PPI and (S)-PPI neutral<br />
100<br />
racemic amine:PEA<br />
50<br />
racemic amine:PEA<br />
12<br />
50<br />
0<br />
0 0.5 1 1.5 2<br />
Γ (mol.mol -1 )<br />
-50<br />
-100<br />
e.e. (cal)<br />
e.e. (exp)<br />
(a)<br />
e.e. ML (cal)<br />
e.e. ML (exp)<br />
100 racemic amine:PPI2<br />
50<br />
0<br />
0 0.5 1 1.5 2<br />
Γ (mol.mol -1 )<br />
-50<br />
-100<br />
e.e. (cal)<br />
e.e. (exp)<br />
(c)<br />
e.e. ML (cal)<br />
e.e. ML (exp)<br />
e.e. (%)<br />
e.e. (%)<br />
Y (%)<br />
(b)<br />
Y (%)<br />
(d)<br />
40<br />
30<br />
20<br />
10<br />
0<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
Y (cal)<br />
pH (cal)<br />
pH (exp)<br />
0<br />
0 0.5 1 1.5 2<br />
racemic amine:PPI2<br />
Y (cal)<br />
pH (cal)<br />
Γ (mol.mol -1 )<br />
Y<br />
Y (exp)<br />
0<br />
0 0.5 1 1.5 2<br />
Γ (mol.mol -1 )<br />
Y (exp)<br />
pH (exp)<br />
Y<br />
pH<br />
pH<br />
10<br />
8<br />
6<br />
4<br />
2<br />
12<br />
10<br />
8<br />
6<br />
4<br />
2<br />
pH pH<br />
Figure 3. Comparison between experimental and modelling results. (a) and (b) show results <strong>for</strong> PEA and (c) and (d) <strong>for</strong> PPI2. Calculated results were<br />
obtained using model II and input parameters given in Table 1. (a) and (c) show <strong>the</strong> ee <strong>for</strong> (S)-enantiomer, <strong>of</strong> <strong>the</strong> obtained solids, and <strong>of</strong> <strong>the</strong> mo<strong>the</strong>r liquor<br />
(ee ML). (b) and (d) show <strong>the</strong> resolution yield, calculated as <strong>the</strong> percentage <strong>of</strong> (S)-amine obtained in <strong>the</strong> solid over <strong>the</strong> <strong>to</strong>tal racemic amine fed <strong>to</strong> <strong>the</strong><br />
resolution [amine] 0 .