Chiral centres, priorities

Groups attached to the chiral centre are given an order of priority according to the sequence rules. For an enantiomeric carbon compound the group of lowest priority is... 

Assign an order of priority, 1, 2, 3, substituents on the chiral centre. 

View the molecule through the chiral centre towards the group of lowest priority, i.e. priority 4. 

We can draw these three stereoisomers as Fischer projections, reversing the configurations at both centres to get the enantiomeric stereoisomers, whilst the Fischer projection for the third isomer, the meso compound, is characterized immediately by a plane of symmetry. For (-l-)-tartaric acid, the configuration is 2R, >R), and for (—)-tartaric acid it is (2S,3S). For both chiral centres, the group of lowest priority is hydrogen, which is on a horizontal line. In fact, this is the case in almost all Fischer projections, since, by convention, the vertical... 

By application of the CIP rules the order of priority of the atoms directly attached to the chirality centre is O > C(0,0,(0)) > C(C,H,H) > H. The atom or group of lowest priority, hydrogen in this case, is already oriented away from the observer. Therefore the sequence of the remaining three groups can be directly deduced from the formula, and these are easily seen to be arranged in a counter-clockwise sense to the observer. It therefore follows that the formula represents (S)-2-hydroxysuccinic acid (formerly known as L-malic acid). The compound is produced in the citric acid cycle from fumaric acid by fumarate-hydratase (fumarase). 

The order of priority of the atoms and groups attached to the chirality centre by application of the CIP rules is N > C(0,0,(0)) > C(H,H,H) > H. The isomer depicted is therefore the unnatural amino acid (R)-alanine, more usually referred to as d-alanine. 

A pseudochirality centre exists on a tetrahedrally coordinated atom when two of the substituents are constitutionally identical but have the opposite chirality sense, i.e. they are enantiomorphic. An R-configured group has priority over an S-configured group. Thus it is possible to determine the configuration of a pseudo chirality centre by application of the sequence rules. To distinguish a pseudo chirality centre from a chirality centre the stereodescriptors r and s are used. 

Adrafinil has a chirality centre since the sulfur atom of the sulfinyl group still possesses an unshared electron pair and consequently can exist with either an R or S configuration. From the sequence rules, the unshared electron pair, which in the S enantiomer shown below is pointing towards the observer, has the lowest priority. The priority order of the groups attached to the sulfur atom is O > C(C,C,H) > C(C,H,H) > e . The mirror image of this formula represents the R isomer. Note that sulfoxides with two different groups attached always have a chirality centre, since the sulfur atom cannot oscillate through the plane (i.e. there is no pyramidal inversion). 

The formula is that of the R isomer of debropol. The priority order of the groups attached to the chirality centre is Br > N02 > CH2OH > CH3. Since the methyl group is already directed away from the observer, the configuration is readily deduced. 

The stereo descriptor Z indicates that the configuration of both chirality centres in a molecule with only two chirality centres is the same. However, this does not give any information about the absolute configuration. Thus Z- 1,2-dichlorocyclobutane can mean a mixture of the enantiomers (R,R) and (S,S)-1,2-dichlorocyclobutane but can also be used for just one of the pure enantiomers. The priority order of the atoms attached to the chirality centres is Cl > C(C1,C,H) > C(C,H,H) > H. 

The stereo descriptor u denotes that two chirality centres are present the configuration of which is unlike. One of these chirality centres is due to the unshared electron pair on the substituted pyramidal sulfur atom. The unshared electron pair is given the lowest priority in determining the configuration. 

The configuration of all the chirality centres is given in the formula shown below. For the chirality centre at position 7 in the ring, the digraph indicates how the priority order is determined. 

Cinchonine contains five chirality centres. Note that because of the rigid structure of the molecule, the nitrogen atom in the quinuclidine ring is also a chirality centre and has the S configuration because the group of lowest priority (the unshared electron pair) is directed towards the observer. 

The compound has the R configuration. Note that the unshared electron pair on the sulfur atom in the formula shown below is oriented towards the observer. Contributions of the sulfur d-orbitals to the S-0 double bond are not considered in the determination of the priority order of the groups attached to the chirality centre. Thus the decyloxy residue has precedence over the doubly bonded oxygen atom. This compound has been used in the synthesis of liquid crystalline substances [6]. 

Fosinopril is a pharmaceutical that, in addition to other chirality centres in the molecule, has a chirality centre at the phosphorus atom. In the determination of the absolute configuration at the phosphorus atom it should be noted that contributions of the phosphorus d-orbitals to the P-0 double bond are not considered. The doubly bonded oxygen atom has therefore a lower priority than the substituted oxygen atom. Note also that fosinopril is a pro-drug whose actual active form, fosinoprilat, results from hydrolysis of the acylal function in the body. It possesses only two chirality centres since the free phosphinic acid is as a consequence of tautomerism configurationally unstable. 

Including the stereoisomer shown, the number of possible stereoisomers is x = 27 = 128 since there are six chirality centres and one double bond which can be either E- or Z-configured. The absolute configuration of the carbon atom at position 4 cannot be determined until the third sphere. In the first sphere there are three carbon atoms, in the second all carbon atoms are attached to two carbon atoms and one hydrogen atom. In the third sphere the priority order is 0,C,C > C,C,(C) > C,C,H and therefore this chirality centre is S- configured. 

Doxycycline contains six chirality centres whose configuration is indicated in the structural formula shown below. The chirality centre at position 12a requires careful consideration since the priority order of the groups attached to this atom may be dependent upon which tautomer is present. As an illustration, if one of the possible tautomers is considered (right hand formula) then the priority order can only be established in the fourth sphere as indicated in the digraph depicted below. 

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