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Stereochemistry Notes

 

A. CIP Rules

Three chemists, R.S.Cahn (England), C.K. Ingold (England), and V. Prelog (Switerland), devised a system of nomenclature that, when added to the IUPAC system, allows to identify a molecule by clearly describing its chiral centers. This system, called the R,S-system or Cahn-Ingold-Prelog (CIP) system, is now widely used and it is part of the IUPAC rules.

The CIP rules assign an order of priority to the four ligands of the chiral center:

 

 

1. Higher atomic number precedes lower.

To apply this rule:

 

a) Substituents are listed in order of decreasing atomic number of the atom directly bonded to the chiral center.

b) When two or more of the atoms connected to the chiral center are identical, the atomic number of the atoms directly bonded to them determines the order. If no difference is encountered the next level of atoms should be considered until a conclusion is achieved.

c) All atoms, except hydrogen, are formally given a valence 4. When the actual valence is less (as in nitrogen, oxygen, or a carbanion), phantom atoms (designated by a subscript 0) are used to bring the valence up to four. These phantom atoms are assigned an atomic number of zero and necessarily rank lowest. Thus the ligand –N+H(CH3)2 ranks higher than –N(CH3)2.

d) Double bond and triple bonds are considered as if they are split into two or three single bonds.

 

 

2. Higher atomic mass precedes lower.

a) A tritium atom (3H) takes precedence over deuterium (2H), which in turn takes precedence over ordinary hydrogen (1H). Similarly, any higher isotope (such as 14C) takes precedence over any lower one (ordinary carbon is 12C).

 

 

 

B. Assign the R or S designation of a molecule

With obchiral tool together with NavMol you can assign the label R or S to the chiral center of a molecule in an MDL Molfile. See how to do common tasks (point five).

 

We show how you can do this for the structure of file S_1.mol.

 
 

You can print the chirality information of S_1 molecule  in S_1.mol file with obchiral tool. Enter:

obchiral S_1.mol”

 

The obchiral will display the messages:

 

“Molecule 1:”

“Atom 2 Is Chiral C3”

“Atom4refs: 1 3 4 5”

“Volume= 2,94711”

“Atom refs= 1 2 3 4”

“Clockwise? 1”

 

And after that, you can immediately know that the S_1 molecule has a chiral carbon atom with id 2, the ordered list is (1 3 4 5) and parity value is 1.

 

With the NavMol, you can know what the four ligands of the chiral center are, and you can assign priorities according to the CIP rules.

 

1) Place the files navmol4h.exe in directory C:/example1

 

Open an MS-DOS window and go to the directory example1 by typing

“C:\” and Press [Enter];

“cd c:\example1” and Press [Enter];

 

Open file S_1.mol with NavMol by entering the following command

“navmol S_1.mol”

 

Now you will use NavMol to navigate the molecule (you can access NavMol notes for documentation of this program).

 

When the molecule loads, NavMol displays the message: “Number of atoms: 5” and “Number of bonds: 4”. It means that the molecule has 5 atoms and 4 bonds.

 

NavMol starts at the atom with id = 1, so a message appears saying: “Current Br1 1 neighbors”. It means the current atom is a bromine atom (Br), with id = 1, and it has 1 neighbor atom.

 

Enter “q” to get information about the neighbor, and you will get: “C2 bond1”. It means that it is a carbon atom (C), with id = 2 and it is bonded to the current bromine atom by a single bond (bond1).

 

Enter “2” to jump to carbon 2 and you will get:” Current C2 4 neighbors”, which means the current atom is now a carbon atom, with id = 2, and it has 3 neighbors. Now you found the chiral atom!

 

Enter “q” to get information about the first neighbor of the current atom, and you get: “X J Br1 bond1”. “X” indicates that this atom has already been visited, and “J” indicates that this is the atom visited immediately before. It is a bromine atom, with id = 1 and connected to the current carbon atom by a single bond.

 

Enter “w” to get information about the second neighbor. You will get the message: “Cl3 bond1”. It is chlorine atom (Cl), with id = 3 connected to the current carbon atom by a single bond.

 

Enter “e” to get information about the third neighbor: “F4 bond1”. The third neighbor is a fluorine atom (F), with id = 4 and connected to the current carbon atom by a single bond.

 

Finally, enter “r” to get information about the fourth neighbor. “H5 bond1”. The fourth neighbor is a hydrogen atom (H), with id = 5 and connected to the current carbon atom by a single bond.

 

At atom number 5 you reached the last atom because you know from the beginning that the molecule has five atoms.

 

Now you have to assign a priority number to each substituent at the chiral center, by the CIP rules (see A.). By application of the CIP rules, the order of the three substituents in descending order of precedence is Br (id 1 is the substituent with the higher priority number), Cl (id 3 is the substituent with the second higher priority number), F (id 4 is the substituent with the third higher priority number) and H (id 5 is the substituent with the fourth higher priority number). Then, the ordered list of priority sequence of the substituents around the tetrahedral carbon atom two is “1 3 4 5”. This is the same ordered list as displayed by obchiral (parity list), so the parity value 1 from obchiral corresponds to the R configuration.

 

If you have doubts that you assign the right R or S label to the S_1 molecule, you can confirm it with IUPAC name or SMILES string.

 

The stereochemical information of S-1 molecule in an MDL Molfile can be obtained by the generation of its IUPAC with molconvert tool.

 

Molconvert command:

 

molconvert name S_1.mol

 

The molconvert will display the message:

 

“(R)-bromo(chloro)fluoromethane”

 

 

The generation of the SMILES string from the S_1 molecule in an MDL Molfile with molconvert or babel also enables the interpretation of the stereochemical features of the S_1 molecule.

 

Molconvert command:

 

molconvert smiles S_1.mol

 

The molconvert will display the message:

 

“[H][C@@](F)(Cl)Br”

 

You should look at the chiral center from the direction of the “from” substituent (the first substituent order in SMILES) and "@@" indicates that the other three substituents are listed clockwise.

 

For the assignment of the R/S label, you should order the substituents by the CIP rules in descending order of precedence - Br is the substituent with the highest priority, Cl is the second, F is the third, and H is the substituent with the lowest priority. Once the four substituents around a center of chirality have been ranked, the R or S configuration can be determined. The molecule has to be held so that the lowest group in the sequence is pointed away from the viewer. In the case of the S_1 molecule, it has to be viewed from the opposite side of the H substituent, i.e. from the opposite side of the requested by the SMILES string. But the CIP rules rank the 3 ligands inversely to the order of the SMILES string. Therefore, when the chiral center is visualized with the H ligand pointing away, the other three ligands ranked according to the CIP rules are ordered clockwise. It means the S_1 molecule has R configuration.

 

 

REFERENCES

  • J. McMurry, Organic Chemistry, 5th ed., Brooks/Cole, 2000.

  • T.W.G. Solomons, C.B. Fryhle, Organic Chemistry, 8th ed., John Wiley & Sons, Hoboken, NJ, 2004.

  • J. March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, New York, 1992.

  • J. Gasteiger; T. Engel, Chemoinformatics: A Textbook, Wiley-VCH, Wienheim, 2003.

  • SMILES Home Page (acessed May 2010).

  • CTfile Formats (accessed May 2010).

 

 

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last update: 03.07.2010