Practical resolution of 1-phenyl-2-(4-methylphenyl)ethylamine using a single resolving agent controlled by the dielectric constant of the solvent

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It is widely believed that the chiral discrimination process is solely dependent on the stereochemistryof the relevant molecules. However, through systematic studies on several resolution systems with popularchiral selectors, we have discovered a new fact that triggers modification of this prevailing conceptof chiral resolution. The studies have demonstrated that one enantiomer of a chiral selector can recognizeboth enantiomers of a target molecule in different solvent systems with different dielectric constants.The phenomenon was termed dielectrically controlled resolution (DCR). Since DCR was observed in differentresolution systems and was not too specific to a particular system, DCR was expected to widely occurin various resolution systems. We have investigated the molecular mechanism underlying this interestingphenomenon based on X-ray analysis of the relevant diastereomeric salts. The disclosed mechanism clearlyindicates that a chiral selector can inherently recognize both enantiomers of a target moleculeand only the dielectric property of the solvent employed in the resolution process governs the selectionof the enantiomer.

Section: X-ray Analysis Of the Diastereomeric Saltssupporting

confidence: 71%

Molecular Mechanisms of Dielectrically Controlled Resolution (DCR)

Sakai

Sakurai

Hirayama

2006

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“…The methods for enantiomeric resolution of racemates comprising nonracemizable enantiomers by crystallization are classified into two categories [17]: one is an indirect method using an external chiral element, such as diastereomeric salt formation followed by fractional crystallization [18][19][20][21][22][23][24][25] or a diastereoselective host-guest inclusion complexation [26,27]; the other is a straightforward method for separating enantiomers by crystallization in the absence of an external chiral element. As a typical example of this latter category, the "preferential crystallization" method is well known to resolve a racemic conglomerate composed of a mixture of homochiral R and S crystals in which, by repeated crystallization from the supersaturated solution with the aid of its enantiopure seed crystals, the enantiomerically enriched crystals are efficiently deposited in the alternating chirality sense [28][29][30][31].…”

Section: Enantiomeric Resolution By Crystallizationmentioning

confidence: 99%

Mechanism and Scope of Preferential Enrichment, a Symmetry-Breaking Enantiomeric Resolution Phenomenon

Tamura

Takahashi

Fujimoto

et al. 2006

The mechanism of "preferential enrichment", an unusually symmetry-breaking enantiomericresolution phenomenon that is observed upon simple recrystallization of a certain kind of organic racemiccrystal from the usual organic solvents without any external chiral element, has been rationalized in termsof a complexity system involving multistage processes that affect each other. These processes comprise:(1) preferential homochiral molecular association to give one-dimensional (1D) R andS chains in solution; (2) formation of γ-form prenucleationaggregates consisting of the same homochiral 1D chains; (3) nucleation and crystal growth of the metastableγ-form crystal composed of irregular alignment of the homochiral 1D R andS chains; (4) the solvent-assisted solid-to-solid type of polymorphictransition of the incipient γ-form crystal into the more stable polymorphic form, such as the α-,δ-, or ε-form; and (5) partial crystal disintegration in the transformed crystal to releaseexcess R or S moleculesinto solution. Based on this mechanism, both induction and inhibition of preferential enrichment have beenachieved by controlling the mode of polymorphic transition during crystallization with appropriate seedcrystals. We call this forced polymorphic transition on the surface of a seed crystal "epitaxialtransition".

“…case-by-case adjustments of intermolecular interactions), whilst sometimes successful at reproducing known experimental structures for specific molecules, lead to limited predictive capability. They also sometimes obscure the real issues (d) (R)-1-phenyl-2-(4-methylphenyl)ethylammonium-(S)-mandelate salt [13]. (e) Progesteronepyrene (2:1) co-crystal [14] 28 C.C.…”

Section: Requirements For General Csp Methodologiesmentioning

confidence: 99%

General Computational Algorithms for Ab Initio Crystal Structure Prediction for Organic Molecules

Pantelides

Adjiman

Kazantsev

2014

The prediction of the possible crystal structure(s) of organic molecules is an important activity for the pharmaceutical and agrochemical industries, among others, due to the prevalence of crystalline products. This chapter considers the general requirements that crystal structure prediction (CSP) methodologies need to fulfil in order to be able to achieve reliable predictions over a wide range of organic systems. It also reviews the current status of a multistage CSP methodology that has recently proved successful for a number of systems of practical interest. Emphasis is placed on recent developments that allow a reconciliation of conflicting needs for, on the one hand, accurate evaluation of the energy of a proposed crystal structure and on the other hand, comprehensive search of the energy landscape for the reliable identification of all low-energy minima. Finally, based on the experience gained from this work, current limitations and opportunities for further research in this area are identified. We also consider issues relating to the use of empirical models derived from experimental data in conjunction with ab initio CSP.