ABSTRACT(+)-(1S;2S)-Pseudoephedrine and racemic mandelic acid form three distinct diastereomeric salts from solutions in 95% ethanol. The least-soluble phase, a hemihydrate, contains the (2R)-mandelate. A salt phase of intermediate solubility is the unsolvated double salt, containing both the (2R)-and the (2S)-mandelate. The mostsoluble salt phase contains the (2S)-mandelate. Mandelate configuration and order of solubility (based on the heats of fusion) is inverted from that found in the same system synthesized from chiral base and acid, and then crystallized from benzene solution. The (2R)-mandelate hemihydrate (−H 2 O at 349.5K, mp 391K), monoclinic, P2 1 , a = 6.788(5), b = 29.415(35), c = 9.488(10)Å,  = 108.91(8)°, Z = 4 (2 ion-pairs/asymmetric unit). Intermediate double salt (2S)-and (2R)-mandelate, mp 377.6K, anorthic, P1, a = 7.758(4), b = 9.966(5), c = 13.366(6)Å, ␣ = 72.99(4),  = 79.98(4), ␥ = 70.51(4)°, Z = 1 (2 ion-pairs/ asymmetric unit). The (2S)-mandelate (mp 386.2K), orthorhombic, P2 1 2 1 2 1 , a = 7.079(6), b = 13.443(10), c = 18.820(14)Å, Z = 4 is identical to a salt made from a combination of enantiomeric moieties from benzene solution. While differing from ephedrine mandelates in configuration at one center, solubilities of pseudoephedrine mandelates in 95% ethanol are much larger. A comparison of molecular structure (non-polar and Hbonding) regions of pseudoephedrine and ephedrine mandelates shows similarities and differences that are tentatively linked to crystal properties. This study reemphasizes the necessity for consistency in solvent use in resolution and in phase identification and comparison because the phases produced are frequently dependent upon the solvent. Chirality 10: 325-337, 1998. © 1998 KEY WORDS: diastereomeric salts; molecular recognition; hydrogen bonding; thermal analysis; crystallography; solubility Intermediate salts from classical resolutions represent a kind of primitive molecular recognition system. In a typical system, a racemic acid forms a pair of diastereomeric salts with a single optically pure base (or vice versa), which are then separated on the basis of solubility.1 If the interionic attractions in such organic salts are the principal cohesive forces, then differences in them between the diastereomers might rationally underlie the physical disparities that permit a macroscopic separation. The (±)-mandelic acid/ (−)-ephedrine system is a good example. In water, its lesssoluble (L) diastereomeric salt has a solubility onethirteenth that of the more-soluble (M) salt and the L-salt's fusion temperature is 70°C higher.2 Realization of such disparities is, at present, essentially a pragmatic enterprise. That is, there is no a priori method for deducing which diastereomeric combinations are likely to be more or less soluble, have lower or higher fusion ranges, and these two properties correlate well with the efficiency of a resolution. Enough experience has been gained from the practice of resolutions that success is not random either.3 Principle component analys...
(+)‐(1S;2S)‐Pseudoephedrine and racemic mandelic acid form three distinct diastereomeric salts from solutions in 95% ethanol. The least‐soluble phase, a hemihydrate, contains the (2R)‐mandelate. A salt phase of intermediate solubility is the unsolvated double salt, containing both the (2R)‐ and the (2S)‐mandelate. The most‐soluble salt phase contains the (2S)‐mandelate. Mandelate configuration and order of solubility (based on the heats of fusion) is inverted from that found in the same system synthesized from chiral base and acid, and then crystallized from benzene solution. The (2R)‐mandelate hemihydrate (−H2O at 349.5K, mp 391K), monoclinic, P21, a = 6.788(5), b = 29.415(35), c = 9.488(10)Å, β = 108.91(8)°, Z = 4 (2 ion‐pairs/asymmetric unit). Intermediate double salt (2S)‐ and (2R)‐mandelate, mp 377.6K, anorthic, P1, a = 7.758(4), b = 9.966(5), c = 13.366(6)Å, α = 72.99(4), β = 79.98(4), γ = 70.51(4)°, Z = 1 (2 ion‐pairs/asymmetric unit). The (2S)‐mandelate (mp 386.2K), orthorhombic, P212121, a = 7.079(6), b = 13.443(10), c = 18.820(14)Å, Z = 4 is identical to a salt made from a combination of enantiomeric moieties from benzene solution. While differing from ephedrine mandelates in configuration at one center, solubilities of pseudoephedrine mandelates in 95% ethanol are much larger. A comparison of molecular structure (non‐polar and H‐bonding) regions of pseudoephedrine and ephedrine mandelates shows similarities and differences that are tentatively linked to crystal properties. This study reemphasizes the necessity for consistency in solvent use in resolution and in phase identification and comparison because the phases produced are frequently dependent upon the solvent. Chirality 10:325–337, 1998. © 1998 Wiley‐Liss, Inc.
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