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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F. C. Ferreira et al. / Tetrahedron: Asymmetry 17 (2006) 1337–1348 1339<br />
Table 1. Model parameters<br />
Entry Amine PEA PPI2<br />
1 Ka 1 (M 1 ) 10 5.2 10 5.2<br />
2 Ka 2 (M 1 ) 10 6.6 10 6.6<br />
3 Ka amine (M 1 ) 10 8.4 10 7.5<br />
4 Kd AS =Kd AR (M) 10 5 10 5<br />
5 Kd AS2 =Kd AR2 (M) 10 10 10 10<br />
6 Ks AR (mM) 2.8 361.0<br />
7 Ks AS (mM) 4.7 12.0<br />
8 Ks AR2 (mM) 387.3 14.0<br />
9 Ks AS2 (mM) 28.3 11.0<br />
10 [Amine] 0 (mM) 176.0 280.0<br />
meric salts as a function <strong>of</strong> C employed. For both models,<br />
<strong>the</strong> calculated results (Fig. 2a and b) show that <strong>for</strong> C < 0.5<br />
(half equivalent method), only <strong>the</strong> neutral <strong>diastereomeric</strong><br />
salts are <strong>for</strong>med. Under this condition, virtually all <strong>the</strong><br />
resolving agent is consumed by <strong>the</strong> <strong>for</strong>mation <strong>of</strong> <strong>diastereomeric</strong><br />
salts (AS2 t =2ÆCÆS 0 and AR2 t =2ÆCÆR 0 ), whereas a<br />
significant part <strong>of</strong> <strong>the</strong> amine is left unreacted in solution<br />
(S t,ML = S 0 Æ(1 2ÆC) or R t,ML = R 0 Æ(1 2ÆC)). For 0.5 <<br />
C < 1.5, a mixture <strong>of</strong> neutral and acid salts is <strong>for</strong>med.<br />
Finally, <strong>for</strong> C > 1.5 only <strong>the</strong> acidic salts (AS and AR) are<br />
<strong>for</strong>med, with virtually all <strong>the</strong> amine consumed by <strong>the</strong><br />
<strong>for</strong>mation <strong>of</strong> <strong>the</strong>se salts, and <strong>the</strong> resolving agent added in<br />
excess is left unreacted in solution. Notice that <strong>the</strong> calculated<br />
pr<strong>of</strong>iles are equal <strong>for</strong> <strong>the</strong> two neutral salts and <strong>for</strong><br />
<strong>the</strong> two acidic salts. This is a direct consequence <strong>of</strong> <strong>the</strong><br />
assumption that <strong>the</strong>re is no chiral recognition in solution<br />
(Assumption 5, see Section 4).<br />
A higher solubility limit (Ks) was found <strong>for</strong> <strong>the</strong> (R)-neutral<br />
salt in <strong>the</strong> case <strong>of</strong> PEA (Table 1, entry 8) and <strong>for</strong> <strong>the</strong><br />
(R)-acid salt in <strong>the</strong> case <strong>of</strong> PPI2 (Table 1, entry 6). There<strong>for</strong>e<br />
it is expected that <strong>the</strong> resolution <strong>of</strong> PEA is based on<br />
<strong>the</strong> differential solubility <strong>of</strong> neutral salts (Ks AR2 and<br />
Ks AS2 ), whereas <strong>the</strong> resolution <strong>of</strong> PPI2 is based on <strong>the</strong><br />
differential solubility <strong>of</strong> acidic salts (Ks AR and Ks AS ).<br />
The calculated ee’s shown in Figure 2c and d illustrate this,<br />
with <strong>the</strong> highest predicted ee’s at C < 0.5 in <strong>the</strong> case <strong>of</strong> PEA<br />
(neutral salt <strong>for</strong>mation), and above C > 1.5 in <strong>the</strong> case <strong>of</strong><br />
PPI2 (acidic salt <strong>for</strong>mation).<br />
The calculated data in Figure 2a and b show a significant<br />
impact <strong>of</strong> <strong>the</strong> acid–base equilibria <strong>for</strong> <strong>the</strong> region <strong>of</strong> acidic<br />
Concentration (M)<br />
(a)<br />
0.16<br />
0.14<br />
0.12<br />
0.10<br />
0.08<br />
0.06<br />
0.04<br />
0.02<br />
Neutral<br />
Salts<br />
AR&AS (Model I)<br />
AR2&AS2 (Model I)<br />
AR&AS (Model II)<br />
AR2&AS2 (Model II)<br />
0.00<br />
0 0.5 1 1.5 2<br />
100<br />
Γ (mol.mol -1 )<br />
Acidic<br />
Salts<br />
AR&AS<br />
(Model II)<br />
AR&AS<br />
(Model I)<br />
AR2&AS2<br />
(Model I)<br />
AR2&AS2<br />
(Model II)<br />
racemic amine: PEA<br />
Concentration (M)<br />
(b)<br />
0.35<br />
0.30<br />
0.25<br />
0.20<br />
0.15<br />
0.10<br />
At (Model I)<br />
Rt (Model I)<br />
St (Model I)<br />
pH (Model II)<br />
0.05<br />
At<br />
2<br />
(Model II)<br />
0.00<br />
0<br />
0 0.5 1 1.5 2<br />
100<br />
Rt&St<br />
(Model I &<br />
Model II)<br />
pH<br />
(Model II)<br />
At<br />
(Model I)<br />
Γ (mol.mol -1 )<br />
racemic amine:PPI2<br />
At (Model II)<br />
Rt (Model II)<br />
St (Model II)<br />
12<br />
10<br />
8<br />
6<br />
4<br />
pH<br />
50<br />
50<br />
e.e. (%)<br />
0<br />
-50<br />
0 0.5 1 1.5 2<br />
Γ (mol.mol -1 )<br />
e.e. (%)<br />
0<br />
-50<br />
0 0.5 1 1.5 2<br />
Γ (mol.mol -1 )<br />
(c)<br />
-100<br />
e.e. (Model I)<br />
e.e. (Model II)<br />
e.e. ML (Model II) e.e. ML (Model I)<br />
(d)<br />
-100<br />
e.e. (Model I)<br />
e.e. ML (Model I)<br />
e.e. (Model II)<br />
e.e. ML (Model II)<br />
Figure 2. Model results comparison. Models I and II, respectively, neglect and account <strong>for</strong> acid–base equilibrium. Results in (a) and (b) were calculated <strong>for</strong><br />
[amine] 0 = 280 mM, but neglecting <strong>the</strong> precipitation <strong>of</strong> any salt, that is, a value <strong>of</strong> zero was fixed <strong>for</strong> W AS , W AR , W AS2 , W AR2 . Results in (c) and (d) were<br />
calculated using input parameters given in Table 1 <strong>for</strong> <strong>the</strong> PEA and PPI2 amine–DTTA systems, respectively.