CIP rules

Early implementations of the CIP rules for computer detection and specification of chirality were described for the LHASA [105], CHIRON [106], and CACTVS [107] software packages. Recently, several commercial molecular editors and visualizers (e.g., CambridgeSoft s ChemOffice, ACD s I-Lab, Accelrys WebLab, and MDL s AutoNom) have also implemented the CIP rules. 

First, both the skeleton and the ligands at a stereocenter have to be numbered independently of each other. The sites of the skeleton can be numbered arbitrarily but then this numbering has to remain fixed all the time in any further operations. The atoms directly bonded to the stereocenter have to be numbered according to rules such as the CIP rules or the Morgan Algorithm (Figure 2-79). 

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

Change in the designation due to CIP rules and not the steric course of the reaction. 

The result of this method is consistent with that obtained by using the corresponding Mosher s ester method (Adn = d(/o-ATMA - (s)-atma) (Fig- 1-25). Note that in the method of Mosher s ester, (Ss — Sr) was applied to calculate Ah) i, the difference in the 2ATMA method is only due to the configuration nomenclature difference caused by the CIP rule. 

Three-dimensional (3-D) descriptors of molecules quantify their shape, size, and other structural characteristics which arise out of the 3-D disposition and orientation of atoms and functional groups of molecules in space. A special class of 3-D indices is quantitative descriptors of chirality. If a molecule has one or more chiral centers, the spatial disposition of atoms can produce enantiomers, many of which will have the same magnitude of calculated and experimental physicochemical properties having, at the same time, distinct bioactivity profiles. Basak and coworkers [22] have developed quantitative chirality indices to discriminate such isomers according to their structural invariants which are based on the Cahn-Ingold-Prelog (CIP) rules. 

According to the CIP rule, different degrees of priorities are assigned to the four chemical groups attached to the chiral carbon, a being given the highest priority,... 

The currently used (R,S)-nomenclature of asymmetric C-atoms and similar tetracoordinate configurations is based upon the sequential order of the ligands derived from the CIP rules. If one orients an asymmetric C-atom in such a manner that the fourth ligand points backwards, the indices of the first three ligands of an (I )-configuration increase in a clockwise pattern, and counterclockwise for an (S)-configuration. 

The (I ,S)-nomenclature still reminds the user of the right and left handed helical pattern arising from Fresnel s 29> interpretation of optical activity. These patterns are characterized by the combination of a translational and a rotational direction. The Ta skeletal symmetry of tetracoordinate systems submits itself to the pictorial models not applicable to other configurational types. The CIP rules may as well be used to define a configurational nomenclature on the basis of the Fischer projection. If one specified that in such a projection of an (R)-... 

In Figure 4.2 we have drawn how we can distinguish the two faces of an alkene, or rather the side of attack of a specific atom of the alkene. The arrow on the left approaches the lower carbon of the alkene and when looking from this viewpoint we count the weight of the three substituents the same way as in the CIP rules. We then see the order 1, 2, and 3 counter-clockwise, and we say that the arrow approaches the carbon atom from the si face. For simplicity we call this the si face of the alkene and in most cases this will do. If all four substituents at the alkene are different we can determine the re/si properties of both carbon atoms and these may be different This results in the nomenclature that an alkene may have a re,re and si,si face or re,si and si,re face. Thus, in the latter case one has to indicate to which atom the label is referring. For any enantiospecific, catalytic reaction (hydrogenation, hydroformylation, polymerisation) it is very convenient to use the re and si indicators in the discussion. 

For Ci bidentate ligand systems there may be exceptions to this explanation, which have been called memory effects [7], That is to say, the cyclohex-2-en-l-ylpalladium complex remembers whether it was formed from the R or the S isomer of the starting acetate Thus the R enantiomer is transformed preferably into the R product (neglecting changes in the atom counting in the CIP rules), and the same for S, because the reaction sequence involves two reversions of configuration. 

The concepts described in points and have not resulted in difficulties, however is not easy to understand. Its meaning, stated in other words, is that a rank established for an atom in a given sphere remains valid for the entire branch that originates from that atom. The problem was brought into focus by Cahn with example 4 (see Table 4), where he first transgressed the CIP rules, but later published an erratum8. This example is discussed here in a very detailed manner (Table 5). 

By comparison with the known values of optical rotation the configuration at C-3 of the predominant enantiomer of the 3-phenylalkanoic acid was R in most cases (CIP rules dependent). Therefore, a bicyclic structure of the dilithio compound, in analogy to that proposed for the deprotonated 3-phenyl-2-propenyl ether21, which is alkylated in a metalloinversive reaction mode seems to be reasonable. 

The (benzoyl-trimethyl-silylamino(phenyl-trimethyl-silyl-phosphano) methylene) phenylphosphane was heated in acetonitrile to 80-90°C. A cyclic product was formed, which readily crystallized and turned out to be of a Z-structure according to the CIP rules ... 

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