Spontaneous resolution

When a racemic compound in solution crystallizes in an enantiomorphic unit cell, thus forming a conglomerate, several possibilities can arise. In the ideal case, the crystals that are formed are of a reasonable size and the enantiomeric forms have distinct geometries. This was the situation that Pasteur encountered with sodium ammonium tartrate tetra-hydrate (2.5), and also that which allowed Wemer to separate by hand the complex [Rh C204)3]K3 (2.24)-K3. It must be noted, however, that even in this case the spontaneous resolution must be accompanied by an asymmetric manual sorting operation. 

This type of resolution is relatively rare, but in some cases it can allow the first few enantiomerically pure crystals to be obtained which can then be used in the crystallization of one enantiomer by entrainment. 

This direct separation of enantiomers is named resolution by entrainment. Kostya-novsky uses the term conglomerator for one element (ion) which is able to initiate the crystallization of a conglomerate instead of a racemic crystal. For example Na is a conglomerator for the NaNELj tartrate salt (2.5) because it is responsible for the formation of a conglomerate while the diammonium tartrate salt crystallizes as a true racemic compound. 

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A particular point of interest included in these hehcal complexes concerns the chirality. The heUcates obtained from the achiral strands are a racemic mixture of left- and right-handed double heUces (Fig. 34) (202). This special mode of recognition where homochiral supramolecular entities, as a consequence of homochiral self-recognition, result from racemic components is known as optical self-resolution (203). It appears in certain cases from racemic solutions or melts (spontaneous resolution) and is often quoted as one of the possible sources of optical resolution in the biological world. On the other hand, the more commonly found process of heterochiral self-recognition gives rise to a racemic supramolecular assembly of enantio pairs (204). 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

The first resolution of an octahedral complex into its enantiomers was achieved in 1911 by A. Werner, who got the Nobel Prize in 1913, with the complex [Co(ethylenediamine)(Cl)(NH3)] [10]. Obviously, resolution is to be considered only in the case of kinetically inert complexes whose enantiomers do not racemize quickly after separation. This is a very important remark since, as noted above, the interesting complexes are those containing exchangeable sites required for catalytic activity and thus more sensitive to racemization. We will not discuss here the very rare cases of spontaneous resolution during which a racemic mixture of complexes forms a conglomerate (the A and A enantiomers crystallize in separate crystals) [11,12]. 

Table 46-1 illustrates the pathophysiology of amenorrhea relative to the organ system(s) involved, as well as the specific condition that results in amenorrhea. Amenorrhea is also a normal side effect that may result from the use of low-dose oral contraceptives (OCs), extended-cycle OC pill use, or depot medroxyprogesterone acetate use.5 Many women may experience delayed return of menses after discontinuation of OCs. Postpill amenorrhea usually is a self-limited condition. Further evaluation for other unrecognized conditions, such as polycystic ovary syndrome (PCOS), should be considered if spontaneous resolution of the amenorrhea does not occur within 3 to 6 months following discontinuation of the OCs.6,7... 

Watchful waiting and safety-net antibiotic prescriptions are approaches being used more frequently to attenuate microbial resistance and avoid unnecessary adverse events and costs of antibiotics. Observation is practiced extensively in Europe and involves monitoring for 48 to 72 hours after diagnosing AOM to see if spontaneous resolution will occur. Observation or delayed antibiotic therapy should be considered only in otherwise healthy children without recurrent disease (Fig. 69-1) and only if proper follow-up and good communication exist between clinicians and the parent/caregiver.4,5,16... 

Treatment guidelines developed by the Sinus and Allergy Health Partnership reflect antibiotic choices that are likely to result in favorable clinical and bacteriologic outcomes based on pathogen distribution, spontaneous resolution rates, and nationwide resistance patterns.310 These guidelines (Figs. 69-3 and 69-4) stratify therapy based on severity of disease and risk of infection with resistant organisms, defined as mild disease in patients with prior antibiotic use within 4 to 6 weeks. Other risk factors for resistance include day-care attendance or frequent... 

In 1979 the bieyclic diol exo-2,ejco-6-dihydroxy-2,6-dimethylbicyclo[3.3.1]nonane (i) was prepared and observed to co-crystallise with various solvents, including ethyl acetate, chloroform, toluene, dioxane, and acetone. A crystal structure determination of the ethyl acetate compound revealed the occurrence of a helical canal host structure, containing ethyl acetate as guest (with 3 1 diol ethyl acetate stoichiometry), and that spontaneous resolution had occurred on crystallisation of the multimolecular inclusion compound 6>. 

Progress in defining new treatments for C. difficile infection has been hindered by the heterogeneous nature of hospital-acquired diarrhea, and in particular by whether colitis and/or pseudomembranous colitis is present in individual cases. Study groups have usually been poorly defined in this context, and given the spontaneous resolution of symptoms in a proportion of cases the true efficacy of treatment approaches often remains uncertain. Enthusiasm to explore new treatment possibilities for C. difficile has been largely fuelled by the apparently high relapse rate of conventional (metronidazole or vancomycin) treatment [138],... 

Selenurane oxides are also one of the hypervalent selenium compounds. Recently, the enantiomers of chiral selenurane oxide 38 were isolated for the first time by enantioselective liquid chromatography of the racemate or by spontaneous resolution occurring during slow evaporation of its acetonitrile solution or slow crystallization from the same solvent.57 The absolute configurations of the enantiomers were determined by X-ray crystallographic analysis (Scheme 17). 

Figure 10 Spontaneous resolution of enantiomers below a critical point, shown diagrammatically in terms of the variation of chemical potential with mole fraction, near the critical point.

Finally, one should be cautioned that, occasionally, substances form chiral single crystals of nearly racemic composition. For example, hexahelicene crystals grown from racemic solutions apparently undergo spontaneous resolution, displaying the enantiomorphic space group P2[2,2, however, the e.e. in the crystal is only —2%. This material (and probably others as well) has a lamellar, twinned structure in which alternating layers, 20 p,m thick, of optically pure (/ )-( + )-and (M)-( — )-hexahelicene are perfectly aligned to build up the observed crystal (266). 

Rg. 11.2 Single crystals of morphologically enantiomeric quartz. Note the mirror symmetry of the facets on the respective crystals. Unlike amino acids, the component silicon dioxide molecules have no chirality. The spontaneous resolution of quartz into crystals of opposite morphological handedness is an example of local symmetry breaking in the environment. 

Spontaneous resolution seems to be a general phenomenon, because it is also observed to occur from solutions of achiral sodium chlorate, which crystallizes into morphologically chiral crystals. In the same way as quartz, however, any given spontaneous crystallization produces nearly equal numbers of left- and right-handed sodium chlorate crystals. The explanation for this behavior is that the primary crystallization nuclei that form throughout a cooling concentrated solution must occur with a random distribution of the two morphological chiralities. 

In 1969 Calvin [64] proposed a scheme for autocatalytic symmetry breaking, which he called stereospecific autocatalysis . Calvin s mechanism has been validated experimentally in the context of the total spontaneous resolution during the crystallization of racemic mixtures. During crystallization, crystals of one enantiomer may spontaneously separate, leaving the other enantiomer in solution. If the possibility of the equilibration of the enantiomers in solution exists and if the enantiomer in solution can convert rapidly to the enantiomer that is crystallizing before crystallization is complete, then the entire racemate may deposit as a single enantiomer. At least half a dozen examples of Calvin s stereospecific autocatalysis involving such... 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

An interesting possibility raised by this experiment is that of spontaneous resolution in chiral monolayers. If this were a reasonably common phenomenon, it would give yet another possible answer to the perennial question of the chiral environment for the primordial stereospecific condensation reaction that produced the first chiral biopolymers. As our knowledge of chiral monolayers develops, we should have a better perspective on the likelihood of a racemic film spontaneously unmixing to produce patches of enantiomeric film at lower surface energy. The relevance of such a result to the origin of terrestrial life problem will have to remain eternally speculative and untestable. 

Pompholyx eczema is a special vesicular type of dermatitis affecting the hands and feet. It can be acute and persistent, characterised by many deep-seated, itchy, clear, tiny blisters. Later there may be scaling, fissures and thickening of the skin. Outbreaks usually last several weeks, and common sites include sides of the fingers, palms and, less often, on the soles. The aim of treatment is to prevent secondary infection and spontaneous resolution is expected within 2 or 3 weeks. If, however, it persists, it may be necessary to use short courses of corticosteroid creams. It is an inflammatory reaction and there is no underlying infective component. 

Anogenital warts (condylomata acuminata) are caused by the human papillomavirus and are usually sexually transmitted. The average incubation period is 2-3 months. During pregnancy, the warts may become more widespread, favouring an even more rapid growth. Spontaneous resolution may occur. However, they tend to recur in some patients. 

NUCLEAR MAGNETIC RESONANCE SPONTANEOUS PROCESS Spontaneous resolution,... 

A process that has been studied widely in relation to phenomena such as chiral symmetry breaking, spontaneous resolution and chiral amplification is the reaction (Fig. 18) of [Co(H20)2 (OH)2Co(en)2 2](S04)2 (denoted 1) with NH4Br to give the chiral complex cA-[CoBr(NH3)(en)2]Br2 (denoted 2). This reaction is historically important, as 2 was one of the first octahedral metal complexes to be resolved into A and A stereoisomers, some years after Werner predicted that octahedral ions M(en)2XY should exist as enantiomeric pairs. 

Lahav, M. and Leiserowitz, L. (1999). Spontaneous resolution from three-dimensional crystals to two-dimensional magic nanoclusters. Angew. Chem. Int. Ed. Engl., 38, 2533-6. 

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